Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

Abstract:

The present invention provides novel compounds having a P2X3 and/or
P2X2/3 receptor antagonistic effect.
A pharmaceutical composition having an analgesic effect or an improving
effect of urination disorder comprising a compound of the formula (I):
##STR00001##
wherein Rh and Rj are taken together to form a bond; Ra
and Rb and/or Rd and Re are taken together to form oxo or
the like; Rc is hydrogen, substituted or unsubstituted alkyl or the
like; Rf is --(CR4aR4b)n--R2; R4a and
R4b are hydrogen, substituted or unsubstituted alkyl or the like;
R2 is substituted or unsubstituted cycloalkyl or the like; n is an
integer of 1 to 4; --Rg is --X--R3; --X-- is --O--, --S-- or
the like; R3 is substituted or unsubstituted cycloalkyl or the like,
or its pharmaceutically acceptable salt or a solvate thereof.

Claims:

1. A compound of the formula (VIII): ##STR00205## wherein Z1 and
Z2 are each independently an oxygen atom, a sulfur atom or
═N--Rx; Rx is a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl; Rc is a hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R4a and R4b are each independently a hydrogen atom or
substituted or unsubstituted alkyl, or R4a and R4b attached to
the same carbon atom are taken together to form oxo or thioxo; n is an
integer of 1 to 4; R2 is substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; --X-- is --O--, --S--,
--N(R5)-- or --(CR5aR5b)--; -L- is --O--, --S--,
--N(R5')-- or --(CR5a'R5b')--; R5 and R5' are
each independently a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, or substituted or unsubstituted acyl; R5a, R5b,
R5a' and R5b' are each independently a hydrogen atom, halogen,
hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy or
substituted or unsubstituted alkenyloxy; ring D is a benzene ring, a
pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring;
carbon atom a and carbon atom b are carbon atoms which constitute ring D;
ring B is an aromatic carbocyclic ring, a non-aromatic carbocyclic ring,
an aromatic heterocyclic ring or a non-aromatic heterocyclic ring; s and
s' are each independently an integer of 0 to 3; and R9 and R9'
are each independently halogen, hydroxy, carboxy, cyano, nitro,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
alkyloxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkenylthio, substituted or unsubstituted
alkynylthio, substituted or unsubstituted acyl, substituted or
unsubstituted alkyloxycarbonyl, substituted or unsubstituted
alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,
substituted or unsubstituted carbamoyl, substituted or unsubstituted
amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl,
substituted sulfinyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted
or unsubstituted non-aromatic heterocyclyloxy, substituted or
unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;
provided that s' is an integer of 1 to 3 when ring B is a cyclopentane
ring, a benzene ring, a tetrahydropyran ring or a piperidine ring, or its
pharmaceutically acceptable salt or a solvate thereof.

2. The compound according to claim 1, wherein -L- is --O--, or its
pharmaceutically acceptable salt or a solvate thereof.

3. The compound according to claim 1, wherein ring B is an aromatic
heterocyclic ring, or its pharmaceutically acceptable salt or a solvate
thereof.

4. The compound according to claim 1 wherein ring B is a thiazole ring,
an isothiazole ring, an oxazole ring, an isoxazole ring, a pyrazole ring,
an imidazole ring, a triazole ring, a furan ring, a thiophene ring, a
thiadiazole ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring,
a pyrazine ring, a pyridazine ring, a triazine ring or a benzoxazole
ring, or its pharmaceutically acceptable salt or a solvate thereof.

5. The compound according to claim 1, wherein ring B is a thiazole ring,
an isothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazole
ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine
ring or a pyridazine ring, or its pharmaceutically acceptable salt or a
solvate thereof.

6. The compound according to claim 1, wherein s' is an integer of 1 to 2,
and at least one of R9' is hydroxy, carboxy, cyano, substituted
alkyl, substituted or unsubstituted carbamoyl, substituted or
unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted
sulfonyl or substituted sulfinyl, or its pharmaceutically acceptable salt
or a solvate thereof.

7. The compound according to claim 1, wherein s' is 1, and R9' is
carboxy or substituted or unsubstituted carbamoyl, or its
pharmaceutically acceptable salt or a solvate thereof.

8. A compound of the formula (IX): ##STR00206## wherein Z1 and
Z2 are each independently an oxygen atom, a sulfur atom or
═N--Rx; Rx is a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl; Rc is a hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R4a and R4b are each independently a hydrogen atom or
substituted or unsubstituted alkyl, or R4a and R4b attached to
the same carbon atom are taken together to form oxo or thioxo; n is an
integer of 1 to 4; R2 is substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; --X-- is --O--, --S--,
--N(R5)-- or --(CR5aR5b)--; R5 is a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, or substituted or unsubstituted
acyl; R5a and R5b are each independently a hydrogen atom,
halogen, hydroxy, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy, or
substituted or unsubstituted alkenyloxy; ring D is a benzene ring, a
pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring;
carbon atom a and carbon atom b are carbon atoms which constitute ring D;
R13a and R13b are each independently a hydrogen atom, halogen,
hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy, or
substituted or unsubstituted alkenyloxy, or R13a and R13b
attached to the same carbon atom are taken together to form oxo or
thioxo; ring E is a cycloalkane ring or a cycloalkene ring; s and s' are
each independently an integer of 0 to 3; and R9 and R9' are
each independently halogen, hydroxy, carboxy, cyano, nitro, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted alkynyl, substituted or unsubstituted alkyloxy,
substituted or unsubstituted alkenyloxy, substituted or unsubstituted
alkynyloxy, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted amino, substituted
or unsubstituted sulfamoyl, substituted sulfonyl, substituted sulfinyl,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or
unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic
heterocyclyloxy, substituted or unsubstituted aryloxy or substituted or
unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a
solvate thereof.

9. The compound according to claim 8, wherein R13a and R13b are
both hydrogen atoms, or its pharmaceutically acceptable salt or a solvate
thereof.

10. The compound according to claim 8, wherein ring E is a cyclopropane
ring, or its pharmaceutically acceptable salt or a solvate thereof.

11. The compound according to claim 1, wherein ring D is a benzene ring,
or its pharmaceutically acceptable salt or a solvate thereof.

12. The compound according to claim 1, wherein carbon atom a is
positioned on ring D in a 1,4 relationship with respect to carbon atom b,
or its pharmaceutically acceptable salt or a solvate thereof.

13. The compound according to claim 1, wherein s and s' are each
independently an integer of 0 to 2; and R9 and R9' are each
independently halogen, hydroxy, carboxy, cyano, nitro, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted
or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,
substituted or unsubstituted alkylthio, substituted or unsubstituted
alkenylthio, substituted or unsubstituted alkynylthio, substituted or
unsubstituted acyl, substituted or unsubstituted alkyloxycarbonyl,
substituted or unsubstituted alkenyloxycarbonyl, substituted or
unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl,
substituted or unsubstituted amino, substituted or unsubstituted
sulfamoyl, substituted sulfonyl or substituted sulfinyl, or its
pharmaceutically acceptable salt or a solvate thereof.

14. A compound of the formula (VII): ##STR00207## wherein Z1 and
Z2 are each independently an oxygen atom, a sulfur atom or
═N--Rx; Rx is a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl; Rc is a hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R4a and R4b are each independently a hydrogen atom or
substituted or unsubstituted alkyl, or R4a and R4b attached to
the same carbon atom are taken together to form oxo or thioxo; n is an
integer of 1 to 4; R2 is substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; --X-- is --O--, --S--,
--N(R5)-- or --(CR5aR5b)--; R5 is a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, or substituted or unsubstituted
acyl; R5a and R5b are each independently a hydrogen atom,
halogen, hydroxy, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy, or
substituted or unsubstituted alkenyloxy; s is an integer of 0 to 3; and
R9 is each independently halogen, hydroxy, carboxy, cyano, nitro,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
alkyloxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkenylthio, substituted or unsubstituted
alkynylthio, substituted or unsubstituted acyl, substituted or
unsubstituted alkyloxycarbonyl, substituted or unsubstituted
alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,
substituted or unsubstituted carbamoyl, substituted or unsubstituted
amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl,
substituted sulfinyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted
or unsubstituted non-aromatic heterocyclyloxy, substituted or
unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy, or
its pharmaceutically acceptable salt or a solvate thereof.

16. The compound according to claim 1, wherein Z1 and Z2 are
both oxygen atoms or both sulfur atoms, or its pharmaceutically
acceptable salt or a solvate thereof.

17. The compound according to claim 1, wherein Z1 and Z2 are
both oxygen atoms, or its pharmaceutically acceptable salt or a solvate
thereof.

18. The compound according to claim 1, wherein Rc is unsubstituted
alkyl, alkyl substituted with one or more substituents selected from
Substituent Group A (Substituent Group A: halogen, cyano, hydroxy,
carboxy, sulfo, substituted or unsubstituted alkyloxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), unsubstituted alkenyl, alkenyl substituted with one or more
substituents selected from Substituent Group A, unsubstituted alkynyl or
alkynyl substituted with one or more substituents selected from
Substituent Group A, or its pharmaceutically acceptable salt or a solvate
thereof.

19. The compound according to claim 1, wherein Rc is unsubstituted
alkyl, alkyl substituted with one or more substituents selected from
Substituent Group B'' (Substituent Group B'': hydroxy, carboxy, sulfo, a
substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, and substituted or unsubstituted
guanidyl), unsubstituted alkenyl, alkenyl substituted with one or more
substituents selected from Substituent Group B'', unsubstituted alkynyl
or alkynyl substituted with one or more substituents selected from
Substituent Group B'', or its pharmaceutically acceptable salt or a
solvate thereof.

20. The compound according to claim 1, wherein Rc is unsubstituted
alkyl, or its pharmaceutically acceptable salt or a solvate thereof.

21. The compound according to claim 1, wherein Rc is
--(CR11aR11b)m-OH; R11a and R11b are each
independently a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, or substituted or unsubstituted
alkynyl, or R11a and R11b together with the carbon atom to
which they are attached form a substituted or unsubstituted cycloalkane
ring, a substituted or unsubstituted cycloalkene ring, or a substituted
or unsubstituted non-aromatic heterocyclic ring; and m is an integer of 2
to 4, or its pharmaceutically acceptable salt or a solvate thereof.

22. The compound according to claim 1, wherein Rc is
--(CR11aR11b)m-OH; R11a is a hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted
or unsubstituted alkynyl; R11b is --(CR12aR12b)u-OH;
R12a and R12b are each independently a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
or substituted or unsubstituted alkynyl; u is an integer of 0 to 2; and m
is an integer of 2 to 4, or its pharmaceutically acceptable salt or a
solvate thereof.

23. The compound according to claim 1, wherein Rc is a group of the
formula: ##STR00208## or its pharmaceutically acceptable salt or a
solvate thereof.

24. The compound according to claim 1, wherein Rc is
--(CR14aR14b)t-N(R15a)(R15b); R14a and R14b
are each independently a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, or substituted or
unsubstituted alkynyl, or R14a and R14b together with the
carbon atom to which they are attached form a substituted or
unsubstituted cycloalkane ring, a substituted or unsubstituted
cycloalkene ring, or a substituted or unsubstituted non-aromatic
heterocyclic ring; t is an integer of 2 to 4; and R15a and R15b
are each independently a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbamoyl, substituted or
unsubstituted sulfamoyl, substituted or unsubstituted acyl, substituted
sulfonyl or substituted sulfinyl; or
--(CR14a'R14b')t'-C(═O)N(R15a')(R15b');
R14a' and R14b' are each independently a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
or substituted or unsubstituted alkynyl or R14a' and R14b'
together with the carbon atom to which they are attached form a
substituted or unsubstituted cycloalkane ring, a substituted or
unsubstituted cycloalkene ring, or a substituted or unsubstituted
non-aromatic heterocyclic ring; t' is an integer of 1 to 4; and
R15a' and R15b' are each independently a hydrogen atom, cyano,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbamoyl, substituted or unsubstituted sulfamoyl, substituted or
unsubstituted acyl, substituted sulfonyl or substituted sulfinyl, or its
pharmaceutically acceptable salt or a solvate thereof.

25. The compound according to claim 1, wherein Rc is a group of the
formula: ##STR00209## wherein R15a, R15b are each
independently a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbamoyl, substituted or
unsubstituted sulfamoyl substituted or unsubstituted acyl, substituted
sulfonyl or substituted sulfinyl; R15a' and R15b' are each
independently a hydrogen atom, cyano, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbamoyl, substituted or
unsubstituted sulfamoyl, substituted or unsubstituted acyl, substituted
sulfonyl or substituted sulfinyl, or its pharmaceutically acceptable salt
or a solvate thereof.

26. The compound according to claim 1, wherein n is 1, or its
pharmaceutically acceptable salt or a solvate thereof.

27. The compound according to claim 1, wherein R4a and R4b are
both hydrogen atoms, or R4a and R4b attached to the same carbon
atom are taken together to form oxo, or its pharmaceutically acceptable
salt or a solvate thereof.

28. The compound according to claim 1, wherein n is 1, and R4a and
R4b are both hydrogen atoms, or its pharmaceutically acceptable salt
or a solvate thereof.

29. The compound according to claim 1, wherein R2 is substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, or its pharmaceutically
acceptable salt or a solvate thereof.

30. The compound according to claim 1, wherein R2 is cycloalkyl
optionally substituted with one or more substituents selected from
Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl,
alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl,
cycloalkynyl, and alkylsilylalkynyl), aryl optionally substituted with
one or more substituents selected from Substituent Group C, or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group C, or its pharmaceutically acceptable salt or a solvate
thereof.

31. The compound according to claim 1, wherein --X-- is --N(R5)--,
and R5 is as defined in claim 1, or its pharmaceutically acceptable
salt or a solvate thereof.

32. The compound according to claim 1, wherein --X-- is --NH--, or its
pharmaceutically acceptable salt or a solvate thereof.

33. A compound of the formula (IV): ##STR00210## wherein Z1,
Z2 and Z3 are each independently an oxygen atom or a sulfur
atom; Rc1 is unsubstituted alkyl, unsubstituted alkynyl, alkyl
substituted with one or more substituents selected from Substituent Group
B (Substituent Group B: halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl
substituted with one or more substituents selected from Substituent Group
B, alkynyl substituted with one or more substituents selected from
Substituent Group B; R4a is a hydrogen atom or substituted or
unsubstituted alkyl; R4b is a hydrogen atom; R6 is substituted
or unsubstituted cycloalkyl, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; R4a' is a hydrogen atom or
substituted or unsubstituted alkyl; R4b' is a hydrogen atom; and
R6' is substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl; provided that 1) a compound wherein Rc1 is
ethyl substituted with substituted or unsubstituted amino, or propyl
substituted with substituted or unsubstituted amino, and R6 and
R6' are both substituted or unsubstituted phenyl, and 2) a compound
wherein Rc1 is unsubstituted oxirane, substituted or unsubstituted
phenyl, or alkyl substituted with unsubstituted acetyl, are excluded, or
its pharmaceutically acceptable salt or a solvate thereof.

34. The compound according to claim 33, wherein Z1, Z2 and
Z3 are oxygen atoms, or its pharmaceutically acceptable salt or a
solvate thereof.

35. The compound according to claim 33, wherein R6 is cycloalkyl
optionally substituted with one or more substituents selected from
Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl,
alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl,
cycloalkynyl, and alkylsilylalkynyl), aryl optionally substituted with
one or more substituents selected from Substituent Group C, or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group C, or its pharmaceutically acceptable salt or a solvate
thereof.

36. The compound according to claim 33, wherein R6' is aryl
optionally substituted with one or more substituents selected from
Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl
optionally substituted with halogen, hydroxy, cyano, alkyloxyimino,
dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally
substituted with cycloalkyl; alkynyl optionally substituted with
cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy,
cycloalkyl, aryl or a non-aromatic heterocyclic group optionally
substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl;
cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl;
a non-aromatic heterocyclic group; and alkylamino), or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group D, or its pharmaceutically acceptable salt or a solvate
thereof.

37. A pharmaceutical composition comprising the compound according to
claim 1, or its pharmaceutically acceptable salt, or a solvate thereof.

38. The pharmaceutical composition according to claim 37, wherein the
composition has a P2X3 and/or P2X2/3 receptor antagonistic
effect.

39. A compound according to claim 1, or its pharmaceutically acceptable
salt, or a solvate thereof for use in a method for treating and/or
preventing a disease related to P2X3 and/or P2X2/3 receptor.

40. A method for treating and/or preventing a disease related to
P2X3 and/or P2X2/3 receptor comprising administering the
compound according to claim 1, or its pharmaceutically acceptable salt,
or a solvate thereof.

41. A pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder comprising a compound of the
formula (I): ##STR00211## wherein (i) Rh and Rj are taken
together to form a bond; Ra and Rb and/or Rd and Re
are taken together to form oxo, thioxo or ═N--Rx; Rx is a
hydrogen atom, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl; Rc
is a hydrogen atom, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted acyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; --Rf is
--(CR4aR4b)n-R2; R4a and R4b are each
independently a hydrogen atom or substituted or unsubstituted alkyl, or
R4a and R4b attached to the same carbon atom are taken together
to form oxo or thioxo; n is an integer of 1 to 4; R2 is substituted
or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
--Rg is --X--R3; --X-- is --O--, --S--, --N(R5)-- or
--(CR5aR5b)--; R3 is substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl; R5
is a hydrogen atom, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, or
substituted or unsubstituted acyl; and R5a and R5b are each
independently a hydrogen atom, halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted
or unsubstituted alkynyloxy, or substituted or unsubstituted alkenyloxy;
or (ii) Rh and Rj are taken together to form a bond; Ra is
a group of --Y--R1a; R1a is a hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl; --Y--
is --O--, --S--, --N(R7)-- or --C(R8aR8b)--; R7 is a
hydrogen atom, substituted or unsubstituted alkyl, or substituted or
unsubstituted acyl; R8a and R8b are each independently a
hydrogen atom, halogen or substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl; Rb
and Rc are taken together to form a bond; Rd and Re are
taken together to form oxo or thioxo; and Rf and Rg are as
defined above (i); or (iii) Ra and Rb, Rd and Re,
and/or Rg and Rh are taken together to form oxo or thioxo;
Rc is unsubstituted alkyl, unsubstituted alkynyl, alkyl substituted
with one or more substituents selected from Substituent Group B
(Substituent Group B: halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl
substituted with one or more substituents selected from Substituent Group
B, or alkynyl substituted with one or more substituents selected from
Substituent Group B; Rf is --(CR4aR4b)--R6; Rj
is --(CR4a'R4b')--R6'; R6 is substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; R6' is substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
R4a, R4b, R4a' and R4b' are each independently a
hydrogen atom, or substituted or unsubstituted alkyl; or (iv) Rj and
Rb are taken together to form a bond; Ra is a group of
--Y--R1a; --Y-- is --O--, --S--, --N(R7)-- or
--C(R8aR8b)--; R1a is a hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl; Rc
is a hydrogen atom, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted acyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; Rd and Re are taken
together to form oxo, thioxo or ═N--Rx; Rx is a hydrogen
atom, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl;
--Rf is --(CR4aR4b)n-R2; R4a and R4b are
each independently a hydrogen atom or substituted or unsubstituted alkyl,
or R4a and R4b attached to the same carbon atom are taken
together to form oxo or thioxo; n is an integer of 1 to 4; R2 is
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl; Rg and Rh are taken together to form
═N--R3; and R3 is substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, provided that 1) a compound
wherein, in (i), --X-- is --NH--, and R3 is cyclohexyl substituted
with guanidyl, and 2) a compound wherein, in (ii), Ra is substituted
phenyl, Rd and Re are taken together to form thioxo, R4a
and R4b are taken together to form oxo, and R3 is unsubstituted
cyclohexyl, are excluded, or its pharmaceutically acceptable salt, or a
solvate thereof.

42. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 41, comprising
the compound of the formula (II): ##STR00212## wherein Z1 and
Z2 are each independently an oxygen atom, a sulfur atom or
═N--Rx; Rx, R4a, R4b, n, R2, X, and R3
are as defined in claim 41; and Rc1 is a hydrogen atom, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or a solvate thereof.

43. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein Z1 and Z2 are both oxygen atoms or both
sulfur atoms, or its pharmaceutically acceptable salt or a solvate
thereof.

44. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder, according to claim 42, comprising
the compound wherein Z1 and Z2 are both oxygen atoms or its
pharmaceutically acceptable salt or a solvate thereof.

45. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein Rc1 is alkyl substituted with one or more
substituents selected from Substituent Group A (Substituent Group A:
halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted
alkyloxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
substituted or unsubstituted guanidyl, substituted or unsubstituted
alkylthio, substituted or unsubstituted alkenylthio, substituted or
unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted
or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), alkenyl substituted with one or more substituents selected from
Substituent Group A, or alkynyl substituted with one or more substituents
selected from Substituent Group A, or its pharmaceutically acceptable
salt or a solvate thereof.

46. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein Rc1 is alkyl substituted with one or more
substituents selected from Substituent Group B' (Substituent Group B':
carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic
group, tetrazolyl, substituted or unsubstituted alkyloxycarbonyl,
substituted or unsubstituted alkenyloxycarbonyl, substituted or
unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl,
substituted or unsubstituted sulfamoyl, substituted or unsubstituted
amino, substituted or unsubstituted imino, and substituted or
unsubstituted guanidyl), alkenyl substituted with one or more
substituents selected from Substituent Group B', or alkynyl substituted
with one or more substituents selected from Substituent Group B', or its
pharmaceutically acceptable salt or a solvate thereof.

47. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 41, comprising
the compound of the formula (III): ##STR00213## wherein Z2 is an
oxygen atom, a sulfur atom or ═N--Rx; and Rx, --Y--,
R1a, R4a, R4b, n, R2, --X-- and R3 are as
defined in claim 41, or its pharmaceutically acceptable salt or a solvate
thereof.

48. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 47, comprising
the compound wherein Z2 is an oxygen atom or a sulfur atom, or its
pharmaceutically acceptable salt or a solvate thereof.

49. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 47, comprising
the compound wherein --Y-- is --O--, or its pharmaceutically acceptable
salt or a solvate thereof.

50. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 47, comprising
the compound wherein R1a is alkyl substituted with one or more
substituents selected from Substituent Group A (Substituent Group A:
halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted
alkyloxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
substituted or unsubstituted guanidyl, substituted or unsubstituted
alkylthio, substituted or unsubstituted alkenylthio, substituted or
unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted
or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocycyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), alkenyl substituted with one or more substituents selected from
Substituent Group A, or alkynyl substituted with one or more substituents
selected from Substituent Group A, or its pharmaceutically acceptable
salt or a solvate thereof.

51. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 47, comprising
the compound wherein R1a is alkyl substituted with one or more
substituents selected from Substituent Group B' (Substituent Group B':
carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic
group, tetrazolyl, substituted or unsubstituted alkyloxycarbonyl,
substituted or unsubstituted alkenyloxycarbonyl, substituted or
unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl,
substituted or unsubstituted sulfamoyl, substituted or unsubstituted
amino, substituted or unsubstituted imino, and substituted or
unsubstituted guanidyl), alkenyl substituted with one or more
substituents selected from Substituent Group B', or alkynyl substituted
with one or more substituents selected from Substituent Group B', or its
pharmaceutically acceptable salt or a solvate thereof.

52. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein n is 1, or its pharmaceutically acceptable salt or a
solvate thereof.

53. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein R4a and R4b are both hydrogen atoms, or
R4a and R4b attached to the same carbon atom are taken together
to form oxo, or its pharmaceutically acceptable salt or a solvate
thereof.

54. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein R2 is substituted or unsubstituted cycloalkyl,
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

55. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein R2 is cycloalkyl optionally substituted with
one or more substituents selected from Substituent Group C (Substituent
Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,
alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and
alkylsilylalkynyl), aryl optionally substituted with one or more
substituents selected from Substituent Group C, or heteroaryl optionally
substituted with one or more substituents selected from Substituent Group
C, or its pharmaceutically acceptable salt or a solvate thereof.

56. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein --X-- is --N(R5)--, and R5 is as defined
in claim 41, or its pharmaceutically acceptable salt or a solvate
thereof.

57. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein --X-- is --NH--, or its pharmaceutically acceptable
salt or a solvate thereof.

58. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein R3 is a group of the formula: ##STR00214##
wherein ring A is an aromatic carbocyclic ring or an aromatic
heterocyclic ring; s is an integer of 0 to 3; and R9 is each
independently halogen, hydroxy, carboxy, cyano, nitro, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted
or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,
substituted or unsubstituted alkylthio, substituted or unsubstituted
alkenylthio, substituted or unsubstituted alkynylthio, substituted or
unsubstituted acyl, substituted or unsubstituted alkyloxycarbonyl,
substituted or unsubstituted alkenyloxycarbonyl, substituted or
unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl,
substituted or unsubstituted amino, substituted or unsubstituted
sulfamoyl, substituted sulfonyl, substituted sulfinyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted
cycloalkenyloxy, substituted or unsubstituted non-aromatic
heterocyclyloxy, substituted or unsubstituted aryloxy or substituted or
unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a
solvate thereof.

59. The pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder according to claim 42, comprising
the compound wherein R3 is aryl optionally substituted with one or
more substituents selected from Substituent Group D (Substituent Group D:
halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy,
cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl;
alkenyl optionally substituted with cycloalkyl; alkynyl optionally
substituted with cycloalkyl; alkyloxy optionally substituted with
halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group
optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl;
cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl;
a non-aromatic heterocyclic group; and alkylamino), or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group D, or its pharmaceutically acceptable salt or a solvate
thereof.

60. A method of producing a compound of the formula (XI): ##STR00215##
wherein Z1 and Z2 are each independently an oxygen atom or a
sulfur atom, Rf1 is a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl; Rc1
is substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; R3 is substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl; X is
--N(R5)--; R5 is a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl or substituted or unsubstituted acyl, or its pharmaceutically
acceptable salt or a solvate thereof, characterized by reacting a
compound of the formula (X): ##STR00216## wherein Z1, Z2,
Rf1 and Rc1 are as defined above; R27 is substituted or
unsubstituted alkyl; and n' is an integer of 0 to 3, or its salt, with a
compound of the formula: R3--X' wherein R3 is as defined above;
--X' is --NH(R5); and R5 is as defined above.

61. The method of producing according to claim 60, wherein Z1 and
Z2 are oxygen atoms.

62. The method of producing according to claim 60, wherein Rf1 is a
group of --(CR4aR4b)n-R2; wherein R4a and R4b
are each independently a hydrogen atom or substituted or unsubstituted
alkyl, or R4a and R4b attached to the same carbon atom are
taken together to form oxo or thioxo; n is an integer of 1 to 4; and
R2 is substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl.

63. The method of producing according to claim 60, wherein Rc1 is
substituted or unsubstituted alkyl.

64. The method of producing according to claim 60, wherein R5 is a
hydrogen atom.

65. The method of producing according to claim 60, wherein R3 is
substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl.

66. A compound of the formula (XII): ##STR00217## wherein Z1 and
Z2 are each independently an oxygen atom or a sulfur atom; Rf1
is a hydrogen atom, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted acyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; Rc1 is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl;
provided that Rc1 is not unsubstituted alkyl, unsubstituted alkenyl
or unsubstituted cycloalkyl when Rf1 is a hydrogen atom; R27 is
substituted or unsubstituted alkyl; and n' is an integer of 0 to 3, or
its pharmaceutically acceptable salt or a solvate thereof.

67. The compound according to claim 66, wherein Z1 and Z2 are
oxygen atoms, or its pharmaceutically acceptable salt or a solvate
thereof.

68. The compound according to claim 66, wherein Rf1 is a group of
--(CR4aR4b)n-R2; wherein R4a and R4b are each
independently a hydrogen atom or substituted or unsubstituted alkyl, or
R4a and R4b attached to the same carbon atom are taken together
to form oxo or thioxo; n is an integer of 1 to 4; and R2 is
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

69. The compound according to claim 66, wherein Rc1 is substituted
or unsubstituted alkyl, or its pharmaceutically acceptable salt or a
solvate thereof.

70. The compound according to claim 66, wherein R5 is a hydrogen
atom, or its pharmaceutically acceptable salt or a solvate thereof.

Description:

TECHNICAL FIELD

[0001] The invention relates to a compound useful for the treatment of
diseases or conditions associated with P2X receptor, specifically to
P2X3 and/or P2X2/3 receptor, and a pharmaceutical composition
having an analgesic effect, an improving effect of urination disorder
comprising such compound.

BACKGROUND ART

[0002] Adenosine triphosphate (ATP) is known to serve as a source of
energy in cells and a substrate of phosphorylation, as well as an
extracellular messenger. It is known that ATP is released from a cell by
various stimulation such as cellular injury, inflammation, nociceptive
stimulus, reduced blood oxygen level, and also known to be released
together with another messenger from a primary sensory nerve terminal,
ATP thus released mediates various extracellular signal transductions
through an ATP receptor (Non-Patent Document 4, Non-Patent Document 5).

[0003] ATP receptor is categorized into ionotropic P2X family and G
protein-coupled P2) family. For P2X family, seven subtypes have been
reported, and a member of this family forms a homo-trimeric structure or
a hetero-trimeric structure together with another member of this subtype
and functions as a non-specific cation channel (Non-Patent Document 6).

[0004] ATP is known to cause pain, and studies with P2X3 knockout and
knockdown methodologies have shown that P2X3 receptor mediates
transmission of chronic pain. P2X3 receptors are expressed in a
specific manner on peripheral sensory nerve to form a homo-complex or
hetero-complex with P2X2 (P2X2/3) (Non-Patent Document 1).

[0005] Later, the compound A-317491 was reported as a specific antagonist
to P2X3 and P2X2/3 receptors. A-317491 is
tri-substituted-N-[(1S)-1,2,3,4-tetrahydro-1-naplithalenyl]benzamide
derivative represented by the formula:

##STR00002##

(Patent Document 1). It was reported to exhibit an antagonist activity to
P2X3 and P2X2/3 receptors and analgesic action in neuropathic
pain model and inflammatory pain model (Non-Patent Document 7). This
indicates that pain sensation is transmitted via P2X3 or P2X2/3
receptor and that a compound having a P2X3 or P2X2/3 receptor
antagonistic effect is useful as an analgesic. Also, compounds that
exhibit P2X3 or P2X2/3 receptor antagonistic effect are
described in Patent Documents 2-7.

[0006] Additionally, it was recently reported that vesical reflex was
strongly reduced in P2X3 knockout mouse (Non-Patent Document 2),
suggesting that a compound having P2X3 antagonistic effect is useful
in the treatment of diseases caused by overactive bladder.

[0007] Patent Documents 8, 9, 10 and 11 disclose compounds having similar
structure to the compounds of the present invention but they do not
disclose analgesic effect and P2X3 or P2X2/3 receptor
antagonistic effect. Non-Patent Document 8 discloses compounds having
similar structure to the compounds of the present invention and having
analgesic effect, but it does not discloses P2X3 or P2X2/3 is
receptor antagonistic effect. Patent Document 12 discloses compounds
having P2X3 receptor antagonistic effect but the structures are
different with those of the compounds of the present invention. Patent
Document 13 discloses compounds having P2X3 or P2X2/3 receptor
antagonistic effect with a triazine structure but in case that a ring
corresponding to ring B of the present application is a cyclopentane
ring, a benzene ring, a tetrahydropyrane ring or a piperizine ring, then
the ring is unsubstituted, and therefore, the structures are different
with those of the present invention.

[0008] Patent Document 14 discloses compounds having a
pyrazolyl-substituted triazine ring but the structures are different with
those of the compound of the formula (XII) of the present invention.
Patent Document 14 does not disclose a process for converting a pyrazolyl
group on a triazine ring into an anilino group by using a pyrazolyl group
as a leaving group.

[0009] Non-Patent Documents 9, 10, 11 and 12 disclose a process for
converting a pyrazolyl group to an anilino group by using a pyrazolyl
group as a leaving group, but do not disclose a process for converting a
pyrazolyl group on a triazine ring into an aniline group.

[0036] The present invention provides a novel compound having a P2X3
and/or P2X2/3 receptor antagonistic effect. It also provides a
pharmaceutical composition having a P2X3 and/or P2X2/3 receptor
antagonistic effect and having an analgesic effect or an improving effect
of urination disorder. Furthermore, it provides methods of producing the
above-mentioned compound or pharmaceutical composition and important
intermediates for the producing methods.

Means for Solving the Problem

[0037] Through their extensive research to solve the aforementioned
problems, the inventors have found novel compounds that bind specifically
to P2X3 and/or P2X2/3 receptor and exhibit an antagonistic
effect, and novel compounds that hind specifically to P2X3 and/or
P2X2/3 receptor. Additionally, they have discovered pharmaceutical
compositions that have P2X3 and/or P2X2/3 antagonistic effect
and having an analgesic effect or an improving effect of urination
disorder. Furthermore, they have found methods for producing the
above-mentioned compound or pharmaceutical composition and important
intermediates for the producing methods.

[0038] The compounds and pharmaceutical compositions encompassed by the
present invention produced excellent results of P2X3 receptor
inhibitory effect, P2X3 receptor inhibitory effect in the presence
of rat serum albumin (hereinafter referred to as RSA) and the like. The
compounds encompassed by the present invention or the pharmaceutical
compositions encompassed by the present invention also produced excellent
results in CYP enzyme inhibition assay, FAT assay, solubility assay,
metabolic stability assay, hERG inhibitory activity assay,
bioavailability assay and/or protein binding assay and the like. The
compounds encompassed by the present invention or the pharmaceutical
composition encompassed by the present invention showed potent analgesic
effect or improving effect of urination disorder.

[0039] This invention relates to

[0040] (1) A compound of the formula (VIII):

##STR00003##

wherein Z1 and Z2 are each independently an oxygen atom, a
sulfur atom or ═N--Rx; Rx is a hydrogen atom, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; Rc is a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted acyl,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl; R4a and R4b are each independently a hydrogen atom
or substituted or unsubstituted alkyl, or R4a and R4b attached
to the same carbon atom are taken together to form oxo or thioxo; n is an
integer of 1 to 4; R2 is substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic, heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl;

--X-- is --O--, --S--, --N(R5)-- or --(CR5aR5b)--;

-L- is --O--, --S--, --N(R5')-- or --(CR5a'R5b')--;

[0041] R5 and R5' are each independently a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, or substituted or unsubstituted
acyl;

[0042] R5a, R5b, R5a' and R5b' are each independently
a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted alkyloxy, substituted or
unsubstituted alkynyloxy or substituted or unsubstituted alkenyloxy; ring
D is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring
or a pyridazine ring;

carbon atom a and carbon atom b are carbon atoms which constitute ring D;
ring B is an aromatic carbocyclic ring, a non-aromatic carbocyclic ring,
an aromatic heterocyclic ring or a non-aromatic heterocyclic ring; s and
s' are each independently an integer of 0 to 3; and R9 and R9'
are each independently halogen, hydroxy, carboxy, cyano, nitro,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
alkyloxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted alkylthio
substituted or unsubstituted alkenylthio, substituted or unsubstituted
alkynylthio, substituted or unsubstituted acyl, substituted or
unsubstituted alkyloxycarbonyl, substituted or unsubstituted
alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,
substituted or unsubstituted carbamoyl, substituted or unsubstituted
amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl,
substituted sulfinyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted
or unsubstituted non-aromatic heterocyclyloxy, substituted or
unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;
provided that s' is an integer of 1 to 3 when ring B is a cyclopentane
ring, a benzene ring, a tetrahydropyran ring or a piperidine ring, or its
pharmaceutically acceptable salt or a solvate thereof.

[0043] (2) The compound according to the above (1), wherein -L- is --O--,
or its pharmaceutically acceptable salt or a solvate thereof.

[0044] (3) The compound according to the above (1) or (2), wherein ring B
is an aromatic heterocyclic ring, or its pharmaceutically acceptable salt
or a solvate thereof.

[0045] (4) The compound according to any one of the above (1) to (3),
wherein ring B thiazole ring, an isothiazole ring, an oxazole ring, an
isoxazole ring, a pyrazole ring, an imidazole ring, a triazole ring, a
furan ring, a thiophene ring, a thiadiazole ring, an oxadiazole ring, a
pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a
triazine ring or a benzoxazole ring, or its pharmaceutically acceptable
salt or a solvate thereof.

[0046] (5) The compound according to any one of the above (1) to (4),
wherein ring B is a thiazole ring, an isothiazole ring, an oxazole ring,
an isoxazole ring, a thiadiazole ring, an oxadiazole ring, a pyridine
ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, or its
pharmaceutically acceptable salt or a solvate thereof.

[0047] (6) The compound according to any one of the above (1) to (5),
wherein s' is an integer of 1 to 2, and at least one of R9' is
hydroxy, carboxy, cyano, substituted alkyl, substituted or unsubstituted
carbamoyl, substituted or unsubstituted amino, substituted or
unsubstituted sulfamoyl, substituted sulfonyl or substituted sulfinyl, or
its pharmaceutically acceptable salt or a solvate thereof.

[0048] (7) The compound according to any one of the above (1) to (6),
wherein s' is 1, and R9' is carboxy or substituted or unsubstituted
carbamoyl, or its pharmaceutically acceptable salt or a solvate thereof.

[0049] (8) A compound of the formula (IX):

##STR00004##

wherein Z1 and Z2 are each independently an oxygen atom, a
sulfur atom or ═N--Rx; Rx is a hydrogen atom, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl; Rc is a hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R4a and R4b are each independently a hydrogen atom or
substituted or unsubstituted alkyl, or R4a and R4b attached to
the same carbon atom are taken together to form oxo or thioxo; n is an
integer of 1 to 4; R2 is substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl;

--X-- is --O--, --S--, --N(R5)-- or --(CR5aR5b)--;

[0050] R5 is a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, or substituted or unsubstituted acyl; R5a and R5b are
each independently a hydrogen atom, halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted
or unsubstituted alkynyloxy, or substituted or unsubstituted alkenyloxy;
ring D is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine
ring or a pyridazine ring; carbon atom a and carbon atom b are carbon
atoms which constitute ring D; R13a and R13b are each
independently a hydrogen atom, halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted
or unsubstituted alkynyloxy, or substituted or unsubstituted alkenyloxy,
or R13a and R13b attached to the same carbon atom are taken
together to form oxo or thioxo; ring E is a cycloalkane ring or a
cycloalkene ring; s and s' are each independently an integer of 0 to 3;
and R9 and R9' are each independently halogen, hydroxy, carboxy
cyano, nitro, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,
substituted or unsubstituted alkynyloxy, substituted or unsubstituted
alkylthio, substituted or unsubstituted alkenylthio, substituted or
unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted
or unsubstituted alkyloxycarbonyl, substituted or unsubstituted
alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,
substituted or unsubstituted carbamoyl, substituted or unsubstituted
amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl,
substituted sulfinyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted
or unsubstituted non-aromatic heterocyclyloxy, substituted or
unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy, or
its pharmaceutically acceptable salt or a solvate thereof.

[0051] (9) The compound according to the above (8), wherein R13a and
R13b are both hydrogen atoms, or its pharmaceutically acceptable
salt or a solvate thereof.

[0052] (10) The compound according to the above (8) or (9), wherein ring E
is a cyclopropane ring, or its pharmaceutically acceptable salt or a
solvate thereof.

[0053] (11) The compound according to any one of the above (1) to (10),
wherein ring D is a benzene ring, or its pharmaceutically acceptable salt
or a solvate thereof.

[0054] (12) The compound according to any one of the above (1) to (11),
wherein carbon atom a is positioned on ring D in a 1,4 relationship with
respect to carbon atom b, or its pharmaceutically acceptable salt or a
solvate thereof.

[0055] (13) The compound according to any one of the above (1) to (12),
wherein s and s' are each independently an integer of 0 to 2; and R9
and R9' are each independently halogen, hydroxy, carboxy, cyano,
nitro, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,
substituted or unsubstituted alkynyloxy, substituted or unsubstituted
alkylthio, substituted or unsubstituted alkenylthio, substituted or
unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted
or unsubstituted alkyloxycarbonyl, substituted or unsubstituted
alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,
substituted or unsubstituted carbamoyl, substituted or unsubstituted
amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or
substituted sulfinyl, or its pharmaceutically acceptable salt or a
solvate thereof.

[0056] (14) A compound of the formula (VII):

##STR00005##

wherein Z1 and Z2 are each independently an oxygen atom, a
sulfur atom or ═N--Rx; Rx is a hydrogen atom, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; Rc is a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted acyl,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl;

[0057] R4a and R4b are each independently a hydrogen atom or
substituted or unsubstituted alkyl, or R4a and R4b attached to
the same carbon atom are taken together to form oxo or thioxo;

n is an integer of 1 to 4; R2 is substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl;

--X-- is --O--, --S--, --N(R5)-- or --(CR5aR5b)--;

[0058] R5 is a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, or substituted or unsubstituted acyl; R5a and R5b are
each independently a hydrogen atom, halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted
or unsubstituted alkynyloxy, or substituted or unsubstituted alkenyloxy;
s is an integer of 0 to 3; and

[0060] (15) The compound according to the above (14), wherein s is an
integer of 0 to 2; and R9 is each independently halogen, hydroxy,
carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,
substituted or unsubstituted alkynyloxy, substituted or unsubstituted
alkylthio, substituted or unsubstituted alkenylthio, substituted or
unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted
or unsubstituted alkyloxycarbonyl, substituted or unsubstituted
alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,
substituted or unsubstituted carbamoyl, substituted or unsubstituted
amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or
substituted sulfinyl, or its pharmaceutically acceptable salt or a
solvate thereof.

[0061] (16) The compound according to any one of the above (1) to (15),
wherein Z1 and Z2 are both oxygen atoms or both sulfur atoms,
or its pharmaceutically acceptable salt or a solvate thereof.

[0062] (17) The compound according to any one of the above (1) to (16),
wherein Z1 and Z2 are both oxygen atoms, or its
pharmaceutically acceptable salt or a solvate thereof.

[0063] (18) The compound according to any one of the above (1) to (17),
wherein Rc is unsubstituted alkyl, alkyl substituted with one or
more substituents selected from Substituent Group A (Substituent Group A:
halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted
alkyloxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
substituted or unsubstituted guanidyl, substituted or unsubstituted
alkylthio, substituted or unsubstituted alkenylthio, substituted or
unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted
or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), unsubstituted alkenyl, alkenyl substituted with one or more
substituents selected from Substituent Group A, unsubstituted alkynyl or
alkynyl substituted with one or more substituents selected from
Substituent Group A, or its pharmaceutically acceptable salt or a solvate
thereof.

[0064] (19) The compound according to any one of the above (1) to (18),
wherein Rc is unsubstituted alkyl, alkyl substituted with one or
more substituents selected from Substituent Group B'' (Substituent Group
B'': hydroxy, carboxy, sulfo, a substituted or unsubstituted non-aromatic
heterocyclic group, tetrazolyl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and substituted or unsubstituted guanidyl), unsubstituted alkenyl,
alkenyl substituted with one or more substituents selected from
Substituent Group B'', unsubstituted alkynyl or alkynyl substituted with
one or more substituents selected from Substituent Group B'', or its
pharmaceutically acceptable salt or a solvate thereof.

[0065] (20) The compound according to any one of the above (1) to (19),
wherein Rc is unsubstituted alkyl, or its pharmaceutically
acceptable salt or a solvate thereof.

[0066] (21) The compound according to any one of the above (1) to (19),
wherein Rc is --(CR11aR11b)m-OH; R11a and R11b
are each independently a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, or substituted or
unsubstituted alkynyl, or R11a and R11b together with the
carbon atom to which they are attached form a substituted or
unsubstituted cycloalkane ring, a substituted or unsubstituted
cycloalkene ring, or a substituted or unsubstituted non-aromatic
heterocyclic ring; and m is an integer of 2 to 4, or its pharmaceutically
acceptable salt or a solvate thereof.

[0067] (22) The compound according to any one of the above (1) to (19) and
(21), wherein Rc is --(CR11aR11b)m-OH; R11a is a
hydrogen atom, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R11b
is --(CR12aR12b)u--OH: R12a and R12b are each
independently a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, or substituted or unsubstituted
alkynyl; u is an integer of 0 to 2; and m is an integer of 2 to 4, or its
pharmaceutically acceptable salt or a solvate thereof.

[0068] (23) The compound according to any one of the above (1) to (19),
(21) and (22), wherein Rc is a group of the formula:

##STR00006##

or its pharmaceutically acceptable salt or a solvate thereof.

[0069] (24) The compound according to any one of the above (1) to (19),
wherein Rc is --(CR14aR14b)t-N(R15a)(R15b);
R14a and R14b are each independently a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
or substituted or unsubstituted alkynyl, or R14a and R14b
together with the carbon atom to which they are attached form a
substituted or unsubstituted cycloalkane ring, a substituted or
unsubstituted cycloalkene ring, or a substituted or unsubstituted
non-aromatic heterocyclic ring; t is an integer of 2 to 4; and R15a
and R15b are each independently a hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbamoyl,
substituted or unsubstituted sulfamoyl, substituted or unsubstituted
acyl, substituted sulfonyl or substituted sulfinyl; or
--(CR14a'R14b')t'-C(═O)N(R15a')(R15b');
R14s' and R14b' are each independently a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
or substituted or unsubstituted alkynyl or R14a' and R14b'
together with the carbon atom to which they are attached form a
substituted or unsubstituted cycloalkane ring, a substituted or
unsubstituted cycloalkene ring, or a substituted or unsubstituted
non-aromatic heterocyclic ring; t' is an integer of 1 to 4; and
R15a' and R15b' are each independently a hydrogen atom, cyano,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbamoyl, substituted or unsubstituted sulfamoyl, substituted or
unsubstituted acyl, substituted sulfonyl or substituted sulfinyl, or its
pharmaceutically acceptable salt or a solvate thereof.

[0070] (25) The compound according to any one of the above (1) to (19),
and (24), wherein Rc is a group of the formula:

##STR00007##

wherein R15a, R15b, R15a' and R15b' are as defined in
the above (24), or its pharmaceutically acceptable salt or a solvate
thereof.

[0071] (26) The compound according to any one of the above (1) to (25),
wherein n is 1, or its pharmaceutically acceptable salt or a solvate
thereof.

[0072] (27) The compound according to any one of the above (1) to (26),
wherein R4a and R4b are both hydrogen atoms, or R4a and
R4b attached to the same carbon atom are taken together to form oxo,
or its pharmaceutically acceptable salt or a solvate thereof.

[0073] (28) The compound according to any one of the above (1) to (27),
wherein n is 1, and R4a and R4b are both hydrogen atoms, or its
pharmaceutically acceptable salt or a solvate thereof.

[0074] (29) The compound according to any one of the above (1) to (28),
wherein R2 is substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or a solvate thereof.

[0075] (30) The compound according to any one of the above (1) to (29),
wherein R2 is cycloalkyl optionally substituted with one or more
substituents selected from Substituent Group C (Substituent Group C:
halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy,
cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), aryl
optionally substituted with one or more substituents selected from
Substituent Group C, or heteroaryl optionally substituted with one or
more substituents selected from Substituent Group C, or its
pharmaceutically acceptable salt or a solvate thereof.

[0076] (31) The compound according to any one of the above (1) to (30),
wherein --X-- is --N(R5)--, and R5 is as defined in the above
(1), or its pharmaceutically acceptable salt or a solvate thereof.

[0077] (32) The compound according to any one of the above (1) to (31),
wherein --X-- is --NH--, or its pharmaceutically acceptable salt or a
solvate thereof.

[0078] (33) A compound of the formula (IV):

##STR00008##

wherein Z1, Z2 and Z3 are each independently an oxygen
atom or a sulfur atom; Rc1 is unsubstituted alkyl, unsubstituted
alkynyl, alkyl substituted with one or more substituents selected from
Substituent Group B (Substituent Group B: halogen, cyano, hydroxy,
carboxy, sulfo, substituted or unsubstituted alkyloxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl
substituted with one or more substituents selected from Substituent Group
B, alkynyl substituted with one or more substituents selected from
Substituent Group B; R4a is a hydrogen atom or substituted or
unsubstituted alkyl; R4b is a hydrogen atom: R6 is substituted
or unsubstituted cycloalkyl, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; R4a' is a hydrogen atom or
substituted or unsubstituted alkyl; R4b' is a hydrogen atom; and

[0079] R6' is substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl; provided that

1) a compound wherein Rc1 is ethyl substituted with substituted or
unsubstituted amino, or propyl substituted with substituted or
unsubstituted amino, and R6 and R6' are both substituted or
unsubstituted phenyl, and

[0081] (34) The compound according to the above (33), wherein Z1,
Z2 and Z3 are oxygen atoms, or its pharmaceutically acceptable
salt or a solvate thereof.

[0082] (35) The compound according to the above (33) or (34), wherein
R6 is cycloalkyl optionally substituted with one or more
substituents selected from Substituent Group C (Substituent Group C:
halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy,
cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), aryl
optionally substituted with one or more substituents selected from
Substituent Group C, or heteroaryl optionally substituted with one or
more substituents selected from Substituent Group C, or its
pharmaceutically acceptable salt or a solvate thereof.

[0083] (36) The compound according to any one of the above (33) to (35),
wherein R6' is aryl optionally substituted with one or more
substituents selected from Substituent Group D (Substituent Group D:
halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy,
cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl;
alkenyl optionally substituted with cycloalkyl; alkynyl optionally
substituted with cycloalkyl; alkyloxy optionally substituted with
halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group
optionally substituted with alkyl: alkylthio; cycloalkyl; cycloalkenyl;
cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl;
a non-aromatic heterocyclic group; and alkylamino), or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group D, or its pharmaceutically acceptable salt or a solvate
thereof.

[0084] (37) A pharmaceutical composition comprising the compound according
to any one of the above (1) to (36), or its pharmaceutically acceptable
salt, or a solvate thereof.

[0085] (38) The pharmaceutical composition according to the above (37),
wherein the composition has a P2X3 and/or P2X2/3 receptor
antagonistic effect.

[0086] (39) A compound according to any one of the above (1) to (36), or
its pharmaceutically acceptable salt, or a solvate thereof for use in a
method for treating and/or preventing a disease related to P2X3
and/or P2X2/3 receptor.

[0087] (40) A method for treating and/or preventing a disease related to
P2X3 and/or P2X2/3 receptor comprising administering the
compound according to any one of the above (1) to (36), or its
pharmaceutically acceptable salt, or a solvate thereof.

[0088] (41) A pharmaceutical composition having an analgesic effect or an
improving effect of urination disorder comprising a compound of the
formula (I):

##STR00009##

wherein (i) Rh and Rj are taken together to form a bond;

[0089] Ra and Rb and/or Rd and Re are taken together
to form oxo, thioxo or ═N--Rx;

--Rf is --(CR4aR4b)n-R2; R4a and R4b are
each independently a hydrogen atom or substituted or unsubstituted alkyl,
or R4a and R4b attached to the same carbon atom are taken
together to form oxo or thioxo; n is an integer of 1 to 4; R2 is
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl;

R5 is a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, or substituted or unsubstituted acyl; and

[0092] R5a and R5b are each independently a hydrogen atom,
halogen, hydroxy, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy, or
substituted or unsubstituted alkenyloxy; or

(ii) Rh and Rj are taken together to form a bond; Ra is a
group of --Y--R1a; R1a is a hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl;

--Y-- is --O--, --S--, --N(R7)-- or --C(R8aR8b)--;

[0093] R7 is a hydrogen atom, substituted or unsubstituted alkyl, or
substituted or unsubstituted acyl; R8a and R8b are each
independently a hydrogen atom, halogen or substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl; Rb
and Rc are taken together to form a bond; Rd and Re are
taken together to form oxo or thioxo; and Rf and Rg are as
defined in the above (i); or (iii) Ra and Rb, Rd and
Re, and/or Rg and Rh are taken together to form oxo or
thioxo: Rc is unsubstituted alkyl, unsubstituted alkynyl, alkyl
substituted with one or more substituents selected from Substituent Group
B (Substituent Group B: halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl
substituted with one or more substituents selected from Substituent Group
B, or alkynyl substituted with one or more substituents selected from
Substituent Group B;

Rf is --(CR4aR4b)--R6;

Rj is --(CR4a'R4b')--R6';

[0094] R6 is substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0095] R6' is substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; and

R4a, R4b, R4a' and R4b' are each independently a
hydrogen atom, or substituted or unsubstituted alkyl; or (iv) Rj and
Rb are taken together to form a bond; Ra is a group of
--Y--R1a;

--Y-- is --O--, --S--, --N(R7)-- or --C(R8aR8b)--;

[0096] R1a is a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl; Rc is
a hydrogen atom, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted acyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; Rd and Re are taken
together to form oxo, thioxo or ═N--R═; Rx is a hydrogen
atom, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl;
--Rf is --(CR4aR4b)n-R2; R4a and R4b are
each independently a hydrogen atom or substituted or unsubstituted alkyl,
or R4a and R4b attached to the same carbon atom are taken
together to form oxo or thioxo; n is an integer of 1 to 4; R2 is
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl; Rg and Rh are taken together to form
═N--R3; and R3 is substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, provided that 1) a compound
wherein, in (i), --X-- is --NH--, and R3 is cyclohexyl substituted
with guanidyl, and 2) a compound wherein, in (ii), Ra is substituted
phenyl, Rd and Ra are taken together to form thioxo, R4a
and R4b are taken together to form oxo, and R3 is unsubstituted
cyclohexyl, are excluded, or its pharmaceutically acceptable salt or a
solvate thereof.

[0097] (42) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to the above (41),
comprising the compound of the formula (II):

##STR00010##

wherein Z1 and Z2 are each independently an oxygen atom, a
sulfur atom or ═N--Rx; Rx, R4a, R4b, n, R2,
X, and R3 are as defined in the above (41); and Rc1 is a
hydrogen atom, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted acyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl, or its pharmaceutically
acceptable salt or a solvate thereof.

[0098] (43) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to the above (42),
comprising the compound wherein Z1 and Z2 are both oxygen atoms
or both sulfur atoms, or its pharmaceutically acceptable salt or a
solvate thereof.

[0099] (44) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder, according to the above (42) or
(43), comprising the compound wherein Z1 and Z2 are both oxygen
atoms or its pharmaceutically acceptable salt or a solvate thereof.

[0100] (45) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (42) to (44), comprising the compound wherein Rc1 is alkyl
substituted with one or more substituents selected from Substituent Group
A (Substituent Group A: halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), alkenyl substituted with one or more substituents selected from
Substituent Group A, or alkynyl substituted with one or more substituents
selected from Substituent Group A, or its pharmaceutically acceptable
salt or a solvate thereof.

[0101] (46) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (42) to (45), comprising the compound wherein Rc1 is alkyl
substituted with one or more substituents selected from Substituent Group
B' (Substituent Group B': carboxy, sulfo, a substituted or unsubstituted
non-aromatic heterocyclic group, tetrazolyl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and substituted or unsubstituted guanidyl), alkenyl substituted with one
or more substituents selected from Substituent Group B', or alkynyl
substituted with one or more substituents selected from Substituent Group
B', or its pharmaceutically acceptable salt or a solvate thereof.

[0102] (47) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to the above (41),
comprising the compound of the formula (III):

##STR00011##

wherein Z2 is an oxygen atom, a sulfur atom or ═N--Rx; and
Rx, --Y--, R1a, R4a, R4b, n, R2, --X-- and
R3 are as defined in the above (41), or its pharmaceutically
acceptable salt or a solvate thereof.

[0103] (48) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to the above (47),
comprising the compound wherein Z2 is an oxygen atom or a sulfur
atom, or its pharmaceutically acceptable salt or a solvate thereof.

[0104] (49) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to the above (47) or
(48), comprising the compound wherein --Y-- is --O--, or its
pharmaceutically acceptable salt or a solvate thereof.

[0105] (50) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (47) to (49), comprising the compound wherein R1a is alkyl
substituted with one or more substituents selected from Substituent Group
A (Substituent Group A: halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocycyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), alkenyl substituted with one or more substituents selected from
Substituent Group A, or alkynyl substituted with one or more substituents
selected from Substituent Group A, or its pharmaceutically acceptable
salt or a solvate thereof.

[0106] (51) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (47) to (50), comprising the compound wherein R1a is alkyl
substituted with one or more substituents selected from Substituent Group
B' (Substituent Group B': carboxy, sulfo, a substituted or unsubstituted
non-aromatic heterocyclic group, tetrazolyl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and substituted or unsubstituted guanidyl), alkenyl substituted with one
or more substituents selected from Substituent Group B', or alkynyl
substituted with one or more substituents selected from Substituent Group
B', or its pharmaceutically acceptable salt or a solvate thereof.

[0107] (52) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (42) to (51), comprising the compound wherein n is 1, or its
pharmaceutically acceptable salt or a solvate thereof.

[0108] (53) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (42) to (52), comprising the compound wherein R4a and R4b
are both hydrogen atoms, or R4a and R4b attached to the same
carbon atom are taken together to form oxo, or its pharmaceutically
acceptable salt or a solvate thereof.

[0109] (54) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (42) to (53), comprising the compound wherein R2 is
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically
acceptable salt or a solvate thereof.

[0110] (55) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (42) to (54), comprising the compound wherein R2 is cycloalkyl
optionally substituted with one or more substituents selected from
Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl,
alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl,
cycloalkynyl, and alkylsilylalkynyl), aryl optionally substituted with
one or more substituents selected from Substituent Group C, or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group C, or its pharmaceutically acceptable salt or a solvate
thereof.

[0111] (56) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (42) to (55), comprising the compound wherein --X-- is
--N(R5)--, and R5 is as defined in the above (41), or its
pharmaceutically acceptable salt or a solvate thereof.

[0112] (57) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (42) to (56), comprising the compound wherein --X-- is --NH--, or
its pharmaceutically acceptable salt or a solvate thereof.

[0113] (58) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (42) to (57), comprising the compound wherein R3 is a group of
the formula:

[0114] (59) The pharmaceutical composition having an analgesic effect or
an improving effect of urination disorder according to any one of the
above (42) to (58), comprising the compound wherein R3 is aryl
optionally substituted with one or more substituents selected from
Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl
optionally substituted with halogen, hydroxy, cyano, alkyloxyimino,
dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally
substituted with cycloalkyl; alkynyl optionally substituted with
cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy,
cycloalkyl, aryl or a non-aromatic heterocyclic group optionally
substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl;
cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl;
a non-aromatic heterocyclic group; and alkylamino), or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group D, or its pharmaceutically acceptable salt or a solvate
thereof.

[0115] (60) A method of producing a compound of the formula (XI):

##STR00013##

wherein Z1 and Z2 are each independently an oxygen atom or a
sulfur atom, Rf1 is a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl; Rc1
is substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; R3 is substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl;

X is --N(R5)--;

[0116] R5 is a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl or substituted or unsubstituted acyl, or its pharmaceutically
acceptable salt or a solvate thereof, characterized by reacting a
compound of the formula (X):

##STR00014##

wherein Z1, Z2, Rf1 and Rc1 are as defined above;
R27 is substituted or unsubstituted alkyl; and n' is an integer of 0
to 3 or its salt, with a compound of the formula: R3--X' wherein
R8 is as defined above;

--X' is --NH(R5); and

[0117] R5 is as defined above. In the above (60), the following
compound of the formula (XII), its pharmaceutically acceptable salt or a
solvate thereof can be used instead of the compound of the formula (X),
its pharmaceutically acceptable salt or a solvate thereof.

[0118] (60') A method of producing a compound of the formula (XVII):

##STR00015##

wherein Z1, Z2, Rc1, R4a, R4b, n, R2, X and
R3 are as defined in the (62) mentioned below, or its
pharmaceutically acceptable salt or a solvate thereof comprising the
steps of i) reacting a compound of the formula (XIII);

##STR00016##

wherein R27 and n' are as defined in the above (60) or its salt with
a compound of the formula:

##STR00017##

wherein Rc is substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted acyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl or its salt in the presence of a
base to give a compound of the formula (XIV):

##STR00018##

wherein Z1, Rc1, R27 and n' are as defined in the above
(60) or its salt, ii) reacting the compound of the formula (XIV) or its
salt with a carbonylating agent or a thiocarbonylating agent in the
presence of a base to give a compound of the formula (XV):

##STR00019##

[0119] wherein Z1, Z2, Rc1, R27 and n' are as defined
in the above (60) or its salt,

iii) reacting the compound of the formula (XV) with a compound of the
formula:

R2--(CR4aR4b)n-Y

wherein R2, R4a, R4b and n are as defined in the (62)
mentioned below and Y is a leaving group or its salt in the presence of a
base to give a compound of the formula (XVI):

##STR00020##

wherein Z1, Z2, Rc1, R4a, R4b, n, R2,
R27 and n' are as defined in the (62) mentioned below or its salt,
and iv) reacting the compound of the formula (XVI) or its salt with a
compound of the formula:

R3--X'

wherein R3 and --X' are as defined in the above (60) or its salt. In
the above (60'), "to give a compound or its salt" includes a case that
the compound or its salt are presence in a reaction system and a case
that the compound or its salt are isolated. In the above (60'), a
compound of the following formula (XII):

##STR00021##

wherein Rf1 is --(CR4aR4b)n-R2 wherein R4a,
R4b, n and R2 are as defined in the (68) mentioned below;
Z1, Z2, Rc1, R27 and n' are as defined in the (66)
mentioned below, or its pharmaceutically acceptable salt or a solvate
thereof can be used instead of the compound of the formula (XVI) or its
pharmaceutically acceptable salt or a solvate thereof.

[0120] (61) The method according to the above (60) or (60'), wherein
Z1 and Z2 are oxygen atoms.

[0121] (62) The method according to any one of the above (60), (60') and
(61), wherein Rf1 is a group of --(CR4aR4b)n-R2;

wherein R4a and R4b are each independently a hydrogen atom or
substituted or unsubstituted alkyl, or R4a and R4b attached to
the same carbon atom are taken together to form oxo or thioxo; n is an
integer of 1 to 4; and R2 is substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl.

[0122] (63) The method according to any one of the above (60), (60'), (61)
and (62), wherein Rc1 is substituted or unsubstituted alkyl.

[0123] (64) The method according to any one of the above (60), (60'), and
(61) to (63), wherein R5 is a hydrogen atom.

[0124] (65) The method according to any one of the above (60), (61'), and
(61) to (64), wherein R3 is substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl.

[0125] (66) A compound of the formula (XII):

##STR00022##

wherein Z1 and Z2 are each independently an oxygen atom or a
sulfur atom; Rf1 is a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl; Rc1
is substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted
or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; provided that Rc1 is not
unsubstituted alkyl, unsubstituted alkenyl or unsubstituted cycloalkyl
when Rf1 is a hydrogen atom: R27 is substituted or
unsubstituted alkyl; and n' is an integer of 0 to 3, or its
pharmaceutically acceptable salt or a solvate thereof.

[0126] (67) The compound according to the above (66), wherein Z1 and
Z2 are oxygen atoms, or its pharmaceutically acceptable salt or a
solvate thereof.

[0127] (68) The compound according to the above (66) or (67), wherein
Rf1 is a group of --(CR4aR4b)n-R2;

wherein R4a and R4b are each independently a hydrogen atom or
substituted or unsubstituted alkyl, or R4a and R4b attached to
the same carbon atom are taken together to form oxo or thioxo; n is an
integer of 1 to 4; and R2 is substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or a solvate thereof.

[0128] (69) The compound according to any one of the above (66) to (68),
wherein Rc1 is substituted or unsubstituted alkyl, or its
pharmaceutically acceptable salt or a solvate thereof.

[0129] (70) The compound according to any one of the above (66) to (69),
wherein R5 is a hydrogen atom, or its pharmaceutically acceptable
salt or a solvate thereof.

Furthermore, the present invention relates to the followings:

[0130] (1B) A pharmaceutical composition having an analgesic effect and/or
an improving effect of urination disorder comprising a compound of the
formula (I):

##STR00023##

wherein (i) Rh and Rj are taken together to form a bond;
Ra and Rb and/or Rd and Re are taken together to form
oxo, thioxo, or ═N--Rx; Rx is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; Rc is hydrogen, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
--Rf is --(CR4aR4b)n-R2; R4a and R4b are
each independently hydrogen, substituted or unsubstituted alkyl, or
R4a and R4b are taken together to form oxo or thioxo; n is an
integer of 1-4; R2 is substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl;

Rg is --X--R3;

--X-- is --O--, --S--, --N(R5)--, or --(CR5aR5b)--;

[0131] R3 is substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; R5 is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl; R5a and
R5b are each independently hydrogen, halogen, hydroxy, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted alkynyl, substituted or unsubstituted alkyloxy,
substituted or unsubstituted alkynyloxy, or substituted or unsubstituted
alkenyloxy; (ii) Rh and Rj are taken together to form a bond;
Ra is a group of --Y--R1a; R1a is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl:

--Y-- is --O--, --S--, --N(R7)--, or --C(R8aR8b)--;

[0132] R7 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted acyl; R8a and R8b are each
independently hydrogen, halogen or substituted or unsubstituted alkyl;
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted acyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; Rb and Rc are taken
together to form a bond; Rd and Re are taken together to form
oxo or thioxo; Rf and Rg are as defined in the above (i); (iii)
Ra and Rb, Rd and Re, and/or Rg and Rh are
taken together to form oxo or thioxo; Rc is unsubstituted alkyl,
unsubstituted alkynyl, alkyl substituted with one or more substituents
selected from Substituent Group B (Substituent Group B: halogen, cyano,
hydroxy, carboxy, sulfo, substituted or unsubstituted alkyloxy,
substituted or unsubstituted alkenyloxy, substituted or unsubstituted
alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted alkyloxycarbonyl,
substituted or unsubstituted alkenyloxycarbonyl, substituted or
unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl,
substituted or unsubstituted sulfamoyl, substituted or unsubstituted
amino, substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl
substituted with one or more substituents selected from Substituent Group
B, or alkynyl substituted with one or more substituents selected from
Substituent Group B;

Rf is --(CR4aR4b)--R6;

Rj is --(CR4a'R4b')--R6';

[0133] R6 is substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl; R6'
is substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl; R4a, R4b, R4a', and R4b' are each
independently hydrogen or substituted or unsubstituted alkyl; (iv)
Rj and Rb are taken together to form a bond; Ra is a group
of --Y--R1a;

Y-- is --O--, --S--, --N(R7)--, or --C(R8aR8b)--;

[0134] R1a is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl: Rc
is hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted acyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; Rd and Re are taken
together to form oxo, thioxo, or ═N--Rx; Rx is hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl; --Rf
is --(CR4aR4b)n-R2; R4a and R4b are each
independently hydrogen, substituted or unsubstituted alkyl, or R4a
and R4b are taken together to form oxo or thioxo; n is an integer of
1 to 4: R2 is substituted or unsubstituted cycloalkyl, substituted
or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; Rg and Rh are taken
together to form ═N--R3; R3 is substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl, provided
that 1) a compound wherein, in (i), --X-- is --NH--, and R3 is
cyclohexyl substituted with guanidyl, and 2) a compound wherein, in (ii),
Ra is substituted phenyl, Rd and Re are taken together to
form thioxo, R4a and R4b are taken together to form oxo, and
R3 is unsubstituted cyclohexyl, are excluded, or its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0135] Furthermore, the present invention relates to the mentioned below.

[0136] (2) A pharmaceutical composition having an analgesic effect and/or
an improving effect of urination disorder comprising the compound of the
formula (II):

##STR00024##

wherein Z1 and/or Z2 is an oxygen atom, a sulfur atom, or
(═)N--Rx; Rx, R4a, R4b, n, R2, X and R3
are as defined in the above (1B); Rc1 is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0137] (3B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (2B) wherein Z1 and/or Z2 is an oxygen
atom or a sulfur atom or its pharmaceutically acceptable salt or a
solvate thereof as an active ingredient.

[0138] (4B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (2B) or (3B) wherein Z1 and Z2 are both
oxygen atoms, its pharmaceutically acceptable salt or a solvate thereof
as an active ingredient.

[0139] (5B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2B) to (4B) wherein Rc1 is alkyl
substituted with one or more substituents selected from Substituent Group
A (Substituent Group A: halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), alkenyl substituted with one or more substituents selected from
Substituent Group A, or alkynyl substituted with one or more substituents
selected from Substituent Group A, its pharmaceutically acceptable salt
or a solvate thereof as an active ingredient.

[0140] (6B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2B) to (5B) wherein Rc1 is alkyl
substituted with one or more substituents selected from Substituent Group
B' (Substituent Group B': carboxy, sulfo, a substituted or unsubstituted
non-aromatic heterocyclic group, tetrazolyl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and substituted or unsubstituted guanidyl), alkenyl substituted with one
or more substituents selected from Substituent Group B', or alkynyl
substituted with one or more substituents selected from Substituent Group
B', or its pharmaceutically acceptable salt or a solvate thereof as an
active ingredient.

[0141] (7B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder according to the above
(1B) comprising the compound of the formula (III):

##STR00025##

wherein Z2 is an oxygen atom, a sulfur atom or (═)N--Rx;
R1, --Y--, R1a, R4a, R4b, n, R2, --X--, and
R3 are as defined in the above (1B) or its pharmaceutically
acceptable salt or a solvate thereof as an active ingredient.

[0142] (8B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (7B) wherein Z2 is an oxygen atom or a sulfur
atom or its pharmaceutically acceptable salt or a solvate thereof as an
active ingredient.

[0143] (9B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (7B) or (8B) wherein --Y-- is --O--, or its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0144] (10B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (7B) to (9B) wherein R1a is alkyl
substituted with one or more substituents selected from Substituent Group
A (Substituent Group A: halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), alkenyl substituted with one or more substituents selected from
Substituent Group A, or alkynyl substituted with one or more substituents
selected from Substituent Group A, or its pharmaceutically acceptable
salt or a solvate thereof as an active ingredient.

[0145] (11B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (7B) to (10B) wherein R1a is alkyl
substituted with one or more substituents selected from Substituent Group
B' (Substituent Group B'; carboxy, sulfo, a substituted or unsubstituted
non-aromatic heterocyclic group, tetrazolyl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and substituted or unsubstituted guanidyl), alkenyl substituted with one
or more substituents selected from Substituent Group B', or alkynyl
substituted with one or more substituents selected from Substituent Group
B', or its pharmaceutically acceptable salt or a solvate thereof as an
active ingredient.

[0146] (12B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2B) to (11B) wherein n is 1, or its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredients.

[0147] (13B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2B) to (12B) wherein R4a and
R4b are both hydrogen atoms or R4a and R4b are taken
together to form oxo, or its pharmaceutically acceptable salt or a
solvate thereof as an active ingredient.

[0148] (14B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2B) to (13B) wherein R2 is
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically
acceptable salt or a solvate thereof as an active ingredient.

[0149] (15B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2B) to (14B) wherein R2 is aryl
optionally substituted with one or more substituents selected from
Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl,
alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl,
cycloalkynyl and alkylsilylalkynyl), heteroaryl optionally substituted
with one or more substituents selected from Substituent Group C or
cycloalkyl optionally substituted with one or more substituents selected
from Substituent Group C, its pharmaceutically acceptable salt or a
solvate thereof as an active ingredient.

[0150] (16B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2B) to (15B) wherein --X-- is
--N(R5)-- wherein R5 is as defined in the above (1B), its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0151] (17B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2B) to (16B) wherein --X-- is --NH--,
or its pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0152] (18B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2B) to (17B) wherein R3 is a
group of the formula:

[0153] (19B) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2B) to (18B) wherein R3 is aryl
optionally substituted with one or more substituents selected from
Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl
optionally substituted with halogen, hydroxy, cyano, alkyloxyimino,
dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally
substituted with cycloalkyl; alkynyl optionally substituted with
cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy,
cycloalkyl, aryl or a non-aromatic heterocyclic group optionally
substituted alkyl; alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy;
aryloxy; heteroaryloxy optionally substituted with alkyl; a non-aromatic
heterocyclic group; and alkylamino), or heteroaryl optionally substituted
with one or more selected from Substituent Group D, or its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0154] (20B) A compound of the formula (IV):

##STR00027##

wherein Z1, Z2, and/or Z3 is an oxygen atom or a sulfur
atom; Rc1 is unsubstituted alkyl, unsubstituted alkynyl, alkyl
substituted with one or more substituents selected from Substituent Group
B (Substituent Group B: halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl
substituted with one or more substituents selected from Substituent Group
B, or alkynyl substituted with one or more substituents selected from
Substituent Group B; R4a is hydrogen or substituted or unsubstituted
alkyl; R4b is hydrogen; R6 is substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl; R4a' is hydrogen or substituted or
unsubstituted alkyl; R4b' is hydrogen; R6' is substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or solvate thereof.

[0155] (21B) The compound according to the above (20B) wherein Z1,
Z2 and Z3 are oxygen atoms, or its pharmaceutically acceptable
salt or a solvate thereof.

[0156] (22B) The compound according to the above (20B) or (21B) wherein
R6 is cycloalkyl optionally substituted with one or more
substituents selected from Substituent Group C (Substituent Group C:
halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy,
cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), aryl
optionally substituted with one or more substituents selected from
Substituent Group C, or heteroaryl optionally substituted with one or
more substituents selected from Substituent Group C, or its
pharmaceutically acceptable salt or a solvate thereof.

[0157] (23B) The compound according to any one of the above (20B) to (22B)
wherein R6' is aryl optionally substituted with one or more
substituents selected from Substituent Group D (Substituent Group D:
halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy,
cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl;
alkenyl optionally substituted with cycloalkyl; alkynyl optionally
substituted with cycloalkyl; alkyloxy optionally substituted with
halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group
optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl;
cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl;
a non-aromatic heterocyclic group; and alkylamino), or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group D, or its pharmaceutically acceptable salt or a solvate
thereof.

[0158] (24B) A compound of the formula (II):

##STR00028##

wherein Z1 and/or Z2 is an oxygen atom, a sulfur atom, or
(═N)--Rx; Rx is hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl. Rc1 is hydrogen, alkyl substituted with
one or more substituents selected from Substituent Group E (Substituent
Group E: sulfo; substituted or unsubstituted sulfamoyl; substituted or
unsubstituted imino; substituted or unsubstituted guanidyl; a substituted
or unsubstituted non-aromatic heterocyclic group provided that
morpholinyl, imidazolidinyl, tetrahydropyranyl and piperidinyl are
excluded; substituted or unsubstituted heteroaryl provided that pyridyl
is excluded), alkenyl substituted with one or more substituents selected
from Substituent Group E, or alkynyl substituted with one or more
substituents selected from Substituent Group E; R4a and R4b are
each independently hydrogen, substituted or unsubstituted alkyl, or
R4a and R4b are taken together to form oxo or thioxo; n is an
integer of 1 to 4; R2 is substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl;

--X-- is --O--, --S--, --N(R5)--, or --(CR5aR5b)--;

[0159] R5 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, or substituted or unsubstituted acyl; R5a and R5b are
each independently hydrogen, halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted
or unsubstituted alkynyloxy, or substituted or unsubstituted alkenyloxy;
R3 is substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl, or substituted or
unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a
solvate thereof.

[0160] (25B) The compound according to the above (24B) wherein Z1
and/or Z2 is an oxygen atom or a sulfur atom, or its
pharmaceutically acceptable salt or a solvate thereof.

[0161] (26B) The compound according to the above (24B) wherein Z1 and
Z2 are both oxygen atoms, its pharmaceutically acceptable salt or a
solvate thereof.

[0162] (27B) The compound according to any one of the above (24B) to (26B)
wherein Rc1 is alkyl substituted with one or more substituents
selected from Substituent Group A (Substituent Group A: halogen, cyano,
hydroxy, carboxy, sulfo, substituted or unsubstituted alkyloxy,
substituted or unsubstituted alkenyloxy, substituted or unsubstituted
alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted alkyloxycarbonyl,
substituted or unsubstituted alkenyloxycarbonyl, substituted or
unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl,
substituted or unsubstituted sulfamoyl, substituted or unsubstituted
amino, substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), alkenyl substituted with one or more substituents selected from
Substituent Group A, or alkynyl substituted with one or more substituents
selected from Substituent Group A, or its pharmaceutically acceptable
salt or a solvate thereof.

[0163] (28B) The compound according to any one of the above (24B) to (27B)
wherein Rc1 is alkyl substituted with one or more substituents
selected from Substituent Group B' (Substituent Group B': carboxy, sulfo,
a substituted or unsubstituted non-aromatic heterocyclic group,
tetrazolyl, substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, and substituted or unsubstituted
guanidyl), alkenyl substituted with one or more substituents selected
from Substituent Group B', or alkynyl substituted with one or more
substituents selected from Substituent Group B', or its pharmaceutically
acceptable salt or a solvate thereof.

[0164] (29B) The compound according to any one of the above (24B) to (28B)
wherein n is 1, or its pharmaceutically acceptable salt or a solvate
thereof.

[0165] (30B) The compound according to any one of the above (24B) to (29B)
wherein R4a and R4b are both hydrogen atoms or R4a and
R4b are taken together to form oxo, or its pharmaceutically
acceptable salt or a solvate thereof.

[0166] (31B) The compound according to any one of the above (24B) to (30B)
wherein R2 is substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or a solvate thereof.

[0167] (32B) The compound according to any one of the above (24B) to (31B)
wherein R2 is aryl optionally substituted with one or more
substituents selected from Substituent Group C (Substituent Group C:
halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy,
cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group C or cycloalkyl optionally substituted with one or more
substituents selected from Substituent Group C, or its pharmaceutically
acceptable salt or a solvate thereof.

[0168] (33B) The compound according to any one of the above (24B) to (33B)
wherein --X-- is --N(R5)-- (wherein R5 is as defined in the
above (1B)), or its pharmaceutically acceptable salt or a solvate
thereof.

[0169] (34B) The compound according to any one of the above (24B) to (33B)
wherein X-- is --NH--, or its pharmaceutically acceptable salt or a
solvate thereof.

[0170] (35B) The compound according to any one of the above (24B) to (34B)
wherein R3 is a group of the formula:

[0171] (36B) The compound according to any one of the above (24B) to (35B)
wherein R3 is aryl optionally substituted with one or more
substituents selected from Substituent Group D (Substituent Group D:
halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy,
cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl;
alkenyl optionally substituted with cycloalkyl; alkynyl optionally
substituted with cycloalkyl; alkyloxy optionally substituted with
halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group
optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl;
cycloalkyloxy aryloxy; heteroaryloxy optionally substituted with alkyl; a
non-aromatic heterocyclic group; and alkylamino) (Substituent Group D:
halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy,
cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl;
alkenyl optionally substituted with cycloalkyl; alkynyl optionally
substituted with cycloalkyl; alkyloxy optionally substituted with
halogen, alkyloxy, aryl or a non-aromatic heterocyclic group optionally
substituted with alkyl: alkylthio; cycloalkyl; cycloalkenyl; aryloxy;
heteroaryloxy: a non-aromatic heterocyclic group; and alkylamino) or
heteroaryl optionally substituted with one or more substituents selected
from Substituent Group D, or its pharmaceutically acceptable salt or a
solvate thereof.

[0172] (37B) A compound of the formula (VII):

##STR00030##

wherein Z1 and/or Z2 is oxo, thioxo, or ═N--Rx;
Rx is hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
Rc is hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted acyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; R4a and R4b are each
independently hydrogen, substituted or unsubstituted alkyl, or R4a
and R4b are taken together to form oxo or thioxo; n is an integer of
1 to 4; R2 is substituted or unsubstituted cycloalkyl, substituted
or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl;

[0174] (38B) The compound according to the above (37B) wherein Z1 and
Z2 are both oxygen atoms, or its pharmaceutically acceptable salt or
a solvate thereof.

[0175] (39B) The compound according to the above (37B) or (38B) wherein
Rc is unsubstituted alkyl, alkyl substituted with one or more
substituents selected from Substituent Group A (Substituent Group A:
halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted
alkyloxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
substituted or unsubstituted guanidyl, substituted or unsubstituted
alkylthio, substituted or unsubstituted alkenylthio, substituted or
unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted
or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), unsubstituted alkenyl, alkenyl substituted with one or more
substituents selected from Substituent Group A, unsubstituted alkynyl,
alkynyl substituted with one or more substituents selected from
Substituent Group A, or its pharmaceutically acceptable salt or a solvate
thereof.

[0176] (40B) The compound according to any one of the above (37B) to (39B)
wherein Rc is unsubstituted alkyl, alkyl substituted with one or
more substituents selected from Substituent Group B'' (Substituent Group
B'': hydroxy, carboxy, sulfo, a substituted or unsubstituted non-aromatic
heterocyclic group, tetrazolyl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and substituted or unsubstituted guanidyl), unsubstituted alkenyl,
alkenyl substituted with one or more substituents selected from
Substituent Group B'', unsubstituted alkynyl, alkynyl substituted with
one or more substituents selected from Substituent Group B'', or its
pharmaceutically acceptable salt or a solvate thereof.

[0177] (41B) The compound according to any one of the above (37B) to (40B)
wherein n is 1 and R4a and R4b are both hydrogen atoms, or its
pharmaceutically acceptable salt or a solvate thereof.

[0178] (42B) The compound according to any one of the above (37B) to (41B)
wherein R2 is substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or a solvate thereof.

[0179] (43B) The compound according to any one of the above (37B) to (42B)
wherein R2 is aryl optionally substituted with one or more
substituents selected from Substituent Group C (Substituent Group C:
halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy,
cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group C or cycloalkyl optionally substituted with one or more
substituents selected from Substituent Group C, or its pharmaceutically
acceptable salt or a solvate thereof given in either of the statements to
either of the above (37B)-(42B).

[0180] (44B) The compound according to any one of the above (37B) to (43B)
wherein --X-- is --N(R5)-- wherein R5 is as defined in the
above (37B), or its pharmaceutically acceptable salt or a solvate
thereof.

[0181] (45B) The compound according to any one of the above (37B) to (44B)
wherein X-- is --NH--, its pharmaceutically acceptable salt or a solvate
thereof.

[0182] (46B) The compound according to any one of the above (37B) to (45B)
wherein s is an integer of 0 to 2, and R9 are each independently,
halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted alkyloxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,
substituted or unsubstituted alkylthio, substituted or unsubstituted
alkenylthio, substituted or unsubstituted alkynylthio, substituted or
unsubstituted acyl, carboxy, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted amino, and
substituted or unsubstituted sulfamoyl), or its pharmaceutically
acceptable salt or a solvate thereof.

[0183] In (46B), a compound wherein s is 0 or 1, or its pharmaceutically
acceptable salt or a solvate thereof is preferable.

R4a and R4b are each independently hydrogen, substituted or
unsubstituted alkyl, or R4a and R4b are taken together to form
oxo or thioxo; n is an integer of 1-4; R2 is substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl; --X--
is --O--, --S--, --N(R5)--, or --(CR5aR5b)--; ring B is
heteroaryl; s and s' are each independently is an integer of 0 to 3;
R9 and R9' are each independently halogen, hydroxy, carboxy,
cyano, nitro, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,
substituted or unsubstituted alkynyloxy, substituted or unsubstituted
alkylthio, substituted or unsubstituted alkenylthio, substituted or
unsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted amino, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or
unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic
heterocyclyloxy, substituted or unsubstituted aryloxy, or substituted or
unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a
solvate thereof.

[0186] (48B) The compound according to the above (47B) wherein Z1 and
Z2 are both oxygen atoms, or its pharmaceutically acceptable salt or
a solvate thereof.

[0187] (49B) The compound according to the above (47B) or (48B) wherein
Rc is unsubstituted alkyl, alkyl substituted with one or more
substituents selected from Substituent Group A (Substituent Group A:
halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted
alkyloxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
substituted or unsubstituted guanidyl, substituted or unsubstituted
alkylthio, substituted or unsubstituted alkenylthio, substituted or
unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted
or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), unsubstituted alkenyl, alkenyl substituted with one or more
substituents selected from Substituent Group A, unsubstituted alkynyl,
alkynyl substituted with one or more substituents selected from
Substituent Group A, or its pharmaceutically acceptable salt or a solvate
thereof.

[0188] (50B) The compound according to any one of the above (47B) to (49B)
wherein Rc is unsubstituted alkyl, alkyl substituted with one or
more substituents selected from Substituent Group B'' (Substituent Group
B'': hydroxy, carboxy, sulfo, a substituted or unsubstituted non-aromatic
heterocyclic group, tetrazolyl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and substituted or unsubstituted guanidyl), unsubstituted alkenyl,
alkenyl substituted with one or more substituents selected from
Substituent Group B'', unsubstituted alkynyl, alkynyl substituted with
one or more substituents selected from Substituent Group B'', or its
pharmaceutically acceptable salt or a solvate thereof.

[0189] (51B) The compound according to any one of the above (47B) to (50B)
wherein n is 1 and R4a and R4b are both hydrogen atoms, or its
pharmaceutically acceptable salt or a solvate thereof.

[0190] (52B) The compound according to any one of the above (47B) to (51B)
wherein R2 is substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or a solvate thereof

[0191] (53B) The compound according to any one of the above (47B) to (52B)
wherein R2 is aryl optionally substituted with one or more
substituents selected from Substituent Group C (Substituent Group C:
halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy,
cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group C, or cycloalkyl optionally substituted with one or
more substituents selected from Substituent Group C, or its
pharmaceutically acceptable salt or a solvate thereof.

[0192] (54B) The compound according to any one of the above (47B) to (53B)
wherein X-- is --N(R5)-- wherein R5 is as defined in the above
(47B), or its pharmaceutically acceptable salt or a solvate thereof.

[0193] (55B) The compound according to any one of the above (47B) to (54B)
wherein X-- is --NH--, or its pharmaceutically acceptable salt or a
solvate thereof.

[0194] (56B) The compound according to any one of the above (47B) to (55B)
wherein ring B is thiazole, isothiazole, oxazole, isoxazole, pyrazole,
imidazole, triazole, furan, thiophene, thiadiazole, oxadiazole, pyridine,
pyrimidine, pyrazine, pyridazine, pyridazine, triazine, or benzoxazole,
or its pharmaceutically acceptable salt or a solvate thereof.

[0195] (57B) The compound according to any one of the above (47B) to (56B)
wherein s and s' are each independently an integer of 0 to 2, and R9
and R9' are each independently halogen, hydroxy, carboxy, cyano,
nitro, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy,
substituted or unsubstituted alkynyloxy, substituted or unsubstituted
alkylthio, substituted or unsubstituted alkenylthio, substituted or
unsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted amino, or substituted or unsubstituted sulfamoyl, or its
pharmaceutically acceptable salt or a solvate thereof.

[0197] (58B) A pharmaceutical composition comprising a compound according
to any one of the above (20B) to (57B), or its pharmaceutically
acceptable salt or a solvate thereof.

[0198] (59B) The pharmaceutical composition according to (58B) wherein the
composition has a P2X3 and/or P2X2/3 receptor antagonistic
effect.

[0199] (60B) A compound according to any one of the above (20B) to (57B)
for use in a method for treating and/or preventing a disease related to
P2X3 and/or P2X2/3 receptor, or its pharmaceutically acceptable
salt or a solvate thereof.

[0200] (61B) A compound according to any one of the above (20B) to (57B)
for use in a method for treating and/or preventing a disease related to
P2X3 and/or P2X2/3 receptor, or its pharmaceutically acceptable
salt or a solvate thereof.

[0201] (62B) A method for treating or preventing a disease related to
P2X3 and/or P2X2/3 receptor, comprising administering the
compound according to any one of the above (20B) to (57B), or its
pharmaceutically acceptable salt or a solvate thereof.

[0202] (1A) A pharmaceutical composition having an analgesic effect and/or
an improving effect of urination disorder comprising the compound of the
formula (I):

##STR00032##

wherein (i) Rh and Rj are taken together to form a bond;
Ra, and Rb, and/or Rd and Re are taken together to
form oxo, thioxo, or ═N--Rx; Rx is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl; Rc is hydrogen, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
--Rf is --(CR4aR4b)n-R2; R4a and R4b are
each independently substituted or unsubstituted alkyl, or R4a and
R4b are taken together to form oxo or thioxo; R2 is substituted
or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

Ra is a group of --Y--R1a; R1a is hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

--Y-- is --O--, --S--, --N(R7)--, or --C(R8aR8b)--;

[0205] R7 is hydrogen, substituted or unsubstituted alkyl, or
substituted or unsubstituted acyl; R8a and R8b are each
independently hydrogen, halogen or substituted or unsubstituted alkyl;
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted acyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; Rb and Rc are taken
together to form a bond; Rd and Re are taken together to form
oxo or thioxo; Rf and Rg are as defined in the above (i); (iii)
Ra and Rb, Rd and Re, and/or Rg and Rh are
taken together to form oxo or thioxo; Rc is unsubstituted alkyl,
unsubstituted alkynyl, alkyl substituted with one or more substituents
selected from Substituent Group B (Substituent Group B: halogen, cyano,
hydroxy, carboxy, sulfo, substituted or unsubstituted alkyloxy,
substituted or unsubstituted alkenyloxy, substituted or unsubstituted
alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic
heterocyclic group, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted alkyloxycarbonyl,
substituted or unsubstituted alkenyloxycarbonyl, substituted or
unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl,
substituted or unsubstituted sulfamoyl, substituted or unsubstituted
amino, substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl and nitro), alkenyl
substituted with one or more substituents selected from Substituent Group
B, or alkynyl substituted with one or more substituents selected from
Substituent Group B;

Rf is --(CR4aR4b)--R6;

Rj is --(CR4a'R4b')--R6';

[0206] R6 is substituted or unsubstituted cycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl; R6' is
substituted or unsubstituted aryl, or substituted or unsubstituted
heteroaryl;

[0207] R4a, R4b, R4a', and R4b' are each independently
hydrogen or substituted or unsubstituted alkyl,

provided that 1) a compound wherein, in (i), --X-- is --NH--, and R3
is cyclohexyl substituted with guanidyl, and 2) a compound wherein, in
(ii), Ra is substituted phenyl, Rd and Re are taken
together to form thioxo, R4a and R4b are taken together to form
oxo, and R3 is unsubstituted cyclohexyl, are excluded. or its
pharmaceutically acceptable salt or solvate thereof as an active
ingredient.

[0208] (2A) A pharmaceutical composition having an analgesic effect and/or
an improving effect of urination disorder comprising the compound of the
formula (II):

##STR00033##

wherein Z1 and/or Z2 is oxo, thioxo, or ═N--Rx;
Rx. R4a, R4b, n, R2, X, and R3 are as defined in
the above (1A); Rc1 is hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0209] (3A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (2A) wherein Z1 and/or Z2 is oxo or
thioxo, or its pharmaceutically acceptable salt or a solvate thereof as
an active ingredient.

[0210] (4A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (2A) or (3A) wherein Z1 and Z2 are both
oxo, or its pharmaceutically acceptable salt or a solvate thereof as an
active ingredient.

[0211] (5A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (4A) wherein Rc1 is alkyl
substituted with one or more substituents selected from Substituent Group
A (Substituent Group A: halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), alkenyl substituted with one or more substituents selected from
Substituent Group A, or alkynyl substituted with one or more substituents
selected from Substituent Group A, or its pharmaceutically acceptable
salt or a solvate thereof as an active ingredient.

[0212] (6A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (5A) wherein Rc1 is alkyl
substituted with one or more substituents selected from Substituent Group
B' (Substituent Group B': carboxy, sulfo, a substituted or unsubstituted
non-aromatic heterocyclic group, tetrazolyl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and substituted or unsubstituted guanidyl), alkenyl substituted with one
or more substituents selected from Substituent Group B', or alkynyl
substituted with one or more substituents selected from Substituent Group
B', or its pharmaceutically acceptable salt or a solvate thereof as an
active ingredient.

[0213] (7A) A pharmaceutical composition having an analgesic effect and/or
an improving effect of urination disorder comprising the compound of the
formula (III):

##STR00034##

wherein Z2 is oxo, thioxo, or ═N--Rx; Rx, --Y--,
R1a, R4a, R4b, n, R2, --X--, and R3 are as
defined in the above (1A); or its pharmaceutically acceptable salt or
solvate thereof as an active ingredient.

[0214] (8A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (7A) wherein Z2 is oxo or thioxo or its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0215] (9A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (7A) or (8A) wherein --Y-- is --O--, or its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0216] (10A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (7A) to (9A) wherein R1a is alkyl
substituted with one or more substituents selected from Substituent Group
A (Substituent Group A: halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl,
substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and
thioxo), alkenyl substituted with one or more substituents selected from
Substituent Group A, or alkynyl substituted with one or more substituents
selected from Substituent Group A, or its pharmaceutically acceptable
salt or a solvate thereof as an active ingredient.

[0217] (11A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (7A) to (10A) wherein R1a is alkyl
substituted with one or more substituents selected from Substituent Group
B' (Substituent Group B': carboxy, sulfo, a substituted or unsubstituted
non-aromatic heterocyclic group, tetrazolyl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and guanidyl), alkenyl substituted with one or more substituents selected
from Substituent Group B', or alkynyl substituted with one or more
substituents selected from Substituent Group B', or its pharmaceutically
acceptable salt or a solvate thereof as an active ingredient.

[0218] (12A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (16A) wherein n is 1, or its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0219] (13A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (12A) wherein R4a and
R4b are both hydrogen, or R4a and R4b are taken together
to form oxo, or its pharmaceutically acceptable salt or a solvate thereof
as an active ingredient.

[0220] (14A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (13A) wherein R2 is
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically
acceptable salt or a solvate thereof as an active ingredient.

[0221] (15A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (2A) to (14A) wherein R2 is aryl optionally
substituted with one or more substituents selected from Substituent Group
C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy,
alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl and
alkylsilylalkynyl), heteroaryl optionally substituted with one or more
substituents selected from Substituent Group C or cycloalkyl optionally
substituted with one or more substituents selected from Substituent Group
C, or its pharmaceutically acceptable salt or a solvate thereof as an
active ingredient.

[0222] (16A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to the above (2A) to (15A) wherein --X-- is --N(R5)--
wherein R5is as defined in the above (1A), or its pharmaceutically
acceptable salt or a solvate thereof as an active ingredient.

[0223] (17A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (16A) wherein --X-- is --NH--,
or its pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0224] (18A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (17A) wherein R3 is a
group of the formula:

[0225] (18A') The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (18A) wherein R3 is a
group of the formula:

[0226] (18A'') The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (18A) and (18A') wherein
R3 is a group of the formula:

##STR00037##

wherein R9a is as defined in the above (18A'); R10 is
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or
unsubstituted non-aromatic heterocyclic group, substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0227] (19A) The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (18A) and (18A') wherein
R3 is aryl optionally substituted with one or more substituents
selected from Substituent Group D (Substituent Group D: halogen; hydroxy;
alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino,
dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally
substituted with cycloalkyl; alkynyl optionally substituted with
cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy,
cycloalkyl, aryl or a non-aromatic heterocyclic group optionally
substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl;
cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alky; a
non-aromatic heterocyclic group; and alkylamino), or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group D, or its pharmaceutically acceptable salt or a solvate
thereof as an active ingredient.

[0228] (19A') The pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
according to any one of the above (2A) to (18A) wherein R3 is a
group of the formula (A):

##STR00038##

wherein ═W1--W2═W3--W4═W5-- is any
one selected from the following (a) to (h):

(a): ═C(H)--C(R10a)═C(R10b)--C(R10c)═C(H)--;

(b): ═N--C(R10a)═C(R10b)--C(R10c)═C(H)--;

(c): ═C(H)--N═C(R10b)--C(R10c)═C(H)--;

(d): ═C(H)--C(R10a)═N--C(R10c)═C(H)--;

(e): ═C(H)--C(R10a)═C(R10b)--N═C(H)--;

(f): ═N--C(R10a)═C(R10b)--C(R10c)═N--;

(g): ═C(H)--C(R10a)═N--C(R10c)═C(H)--; and

(h): ═C(H)--N═C(R10b)--N═C(H)--;

[0229] R10a, R10b, and R10c are each independently
hydrogen, halogen, hydroxy, cyano, nitro, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted alkyloxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,
substituted or unsubstituted alkylthio, substituted or unsubstituted
alkenylthio, substituted or unsubstituted alkynylthio, substituted or
unsubstituted acyl, carboxy, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted amino, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted
or unsubstituted non-aromatic heterocyclyloxy, substituted or
unsubstituted aryloxy, or substituted or heteroaryloxy; or R10a and
R10b or R10b and R10C together with the ring atom to which
they are attached form a non-aromatic carbocyclic ring, a non-aromatic
heterocyclic ring, an aromatic carbocyclic ring or an aromatic
heterocyclic ring, or its pharmaceutically acceptable salt or a solvate
thereof as an active ingredient.

[0230] (19A'') A compound described in any one of the above (1A) to (19A),
(18A'), (18A'') and (19A') for use in a method for treating, preventing
and/or improving pain and/or urination disorder, or its pharmaceutically
acceptable salt or a solvate thereof.

[0231] (19A''') A method for treating, preventing and/or improving pain
and/or urination disorder comprising administering the compound described
in any one of the above (1A) to (19A), (18A'), (18A'') and (19A'), or its
pharmaceutically acceptable salt or a solvate thereof.

[0232] (20A) A compound of the formula (IV):

##STR00039##

wherein Z1, Z2, and/or Z3 is an oxygen atom or a sulfur
atom; Rc1 is unsubstituted alkyl, unsubstituted alkynyl, alkyl
substituted with one or more substituents selected from Substituent Group
B, alkenyl substituted with one or more substituents selected from
Substituent Group B, or alkynyl substituted with one or more substituents
selected from Substituent Group B; R4a is hydrogen or substituted or
unsubstituted alkyl; R4b is hydrogen; R6 is substituted or
unsubstituted cycloalkyl, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl; R4a' is hydrogen or
substituted or unsubstituted alkyl;

[0233] R4b' is hydrogen;

[0234] R6' is substituted or unsubstituted aryl or substituted or
unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a
solvate thereof.

[0235] (21A) The compound according to the above (20A) wherein Z1,
Z2, and Z3 are oxygen atoms, or its pharmaceutically acceptable
salt or a solvate thereof.

[0236] (22A) The compound according to the above (20A) or (22A) wherein
R6 is cycloalkyl optionally substituted with one or more
substituents selected from Substituent Group C, aryl optionally
substituted with one or more substituents selected from Substituent Group
C, or heteroaryl optionally substituted with one or more substituents
selected from Substituent Group C, or its pharmaceutically acceptable
salt or a solvate thereof.

[0237] (23A) The compound according to any one of the above (20A) to (22A)
wherein R6' is aryl optionally substituted with one or more
substituents selected from Substituent Group D, or heteroaryl optionally
substituted with one or more substituents selected from Substituent Group
D, or its pharmaceutically acceptable salt or a solvate thereof.

[0238] (24A) A compound of the formula (II):

##STR00040##

wherein Z1 and/or Z2 is oxo, thioxo, or ═N--Rx;
Rx, R4a, R4b, n, R2, X and R3 are as defined in
the above (1A); Rc1 is hydrogen, alkyl substituted with one or more
substituents selected from Substituent Group E (Substituent Group E:
sulfo: substituted or unsubstituted sulfamoyl; substituted or
unsubstituted, imino; substituted or unsubstituted guanidyl; a
substituted or unsubstituted non-aromatic heterocyclic group provided
that morpholinyl, imidazolidinyl, tetrahydropyranyl and piperidinyl are
excluded; and substituted or unsubstituted heteroaryl provided that
pyridyl are excluded), alkenyl substituted with one or more substituents
selected from Substituent Group E, or alkynyl substituted with one or
more substituents selected from Substituent Group E, or its
pharmaceutically acceptable salt or a solvate thereof.

[0239] (25A) The compound according to the above (24A) wherein Z1
and/or Z2 is oxo or thioxo, or its pharmaceutically acceptable salt
or a solvate thereof.

[0240] (26A) The compound according to the above (24A) or (25A) wherein
Z1 and Z2 are both oxo, or its pharmaceutically acceptable salt
or a solvate thereof.

[0241] (27A) The compound according to any one of the above (24A) to (26A)
wherein Rc1 is alkyl substituted with one or more substituents
selected from Substituent Group B' (Substituent Group B': carboxy, sulfo,
a substituted or unsubstituted non-aromatic heterocyclic group,
tetrazolyl, substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, and substituted or unsubstituted
guanidyl), alkenyl substituted with one or more substituents selected
from Substituent Group B', or alkynyl substituted with one or more
substituents selected from Substituent Group B', or its pharmaceutically
acceptable salt or a solvate thereof.

[0242] (28A) The compound according to any one of the above (24A) to (27A)
wherein n is 1, or its pharmaceutically acceptable salt or a solvate
thereof.

[0243] (29A) The compound according to any one of the above (24A) to (28A)
wherein R4a and R4b are both hydrogen atoms or R4a and
R4b are taken together to form oxo, or its pharmaceutically
acceptable salt or a solvate thereof.

[0244] (30A) The compound according to any one of the above (24A) to (29A)
wherein R2 is substituted or unsubstituted cycloalkyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its
pharmaceutically acceptable salt or a solvate thereof.

[0245] (31A) The compound according to any one of the above (24A) to (30A)
wherein R2 is aryl substituted with one or more substituents
selected from Substituent Group C (Substituent Group C: halogen, alkyl,
alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl,
cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), heteroaryl optionally
substituted with one or more substituents selected from Substituent Group
C or cycloalkyl optionally substituted with one or more substituents
selected from Substituent Group C, or its pharmaceutically acceptable
salt or a solvate thereof.

[0246] (32A) The compound according to any one of the above (24A) to (31A)
wherein --X-- is --N(R5)-- wherein R5 is as defined in the
above (1A), or its pharmaceutically acceptable salt or a solvate thereof.

[0247] (33A) The compound according to any one of the above (24A) to (32A)
wherein X-- is --NH--, or its pharmaceutically acceptable salt or a
solvate thereof.

[0248] (34A) The compound according to any one of the above (24A) to (33A)
wherein R3 is a group of the formula:

##STR00041##

wherein ring A is aryl or heteroaryl; s is an integer of 0 to 3; R9
are each independently halogen, hydroxy, cyano, nitro, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted
or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,
substituted or unsubstituted alkylthio, substituted or unsubstituted
alkenylthio, substituted or unsubstituted alkynylthio, substituted or
unsubstituted acyl, carboxy, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted amino, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted
or unsubstituted non-aromatic heterocyclyloxy, substituted or
unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy, or
its pharmaceutically acceptable salt or a solvate thereof according to
any one of the above (24A) to (33A).

[0249] (34A') The compound according to any one of the above (24A) to
(34A) wherein R3 is a group of the formula:

[0250] (34A'') The compound according to any one of the above (24A) to
(34A) and (34A') wherein R3 is a group of the formula:

##STR00043##

wherein R9 is as defined in the above (7A); R10 is substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted
or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl, or
substituted or unsubstituted heteroaryl, or its pharmaceutically
acceptable salt or a solvate thereof.

[0251] (35A) The compound according to any one of the above (24A) to
(34A), (34A') and (34A'') wherein R3 is aryl optionally substituted
with one or more substituents selected from Substituent Group D
(Substituent Group D: halogen; hydroxy; alkyl optionally substituted with
halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy,
cycloalkyl, or heteroaryl; alkenyl optionally substituted with
cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy
optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a
non-aromatic heterocyclic group optionally substituted with alkyl;
alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy; aryloxy;
heteroaryloxy optionally substituted with alkyl; a non-aromatic
heterocyclic group; and alkylamino), or heteroaryl optionally substituted
with one or more substituents selected from Substituent Group D, or its
pharmaceutically acceptable salt or a solvate thereof.

[0252] (36A) A compound of the following formula:

##STR00044## ##STR00045## ##STR00046##

or its pharmaceutically acceptable salt or a solvate thereof.

[0253] (36A') A compound of the following formula:

##STR00047## ##STR00048##

or its pharmaceutically acceptable salt or a solvate thereof.

[0254] (36A'') A compound of the following formula:

##STR00049## ##STR00050##

its pharmaceutically acceptable salt or a solvate thereof.

[0255] (36A''') A pharmaceutical composition having an analgesic effect
and/or an improving effect of urination disorder comprising the compound
of the following formula:

##STR00051## ##STR00052## ##STR00053## ##STR00054##

or its pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

[0256] (37A) A pharmaceutical composition comprising the compound
according to any one of the above (20A) to (36A), (35A'), (36A'), (35A'')
and (36A''), or its pharmaceutically acceptable salt or a solvate
thereof.

[0257] (37A') A pharmaceutical composition comprising the compound
according to any one of the above (20A) to (36A), (35A'), (36A'), (35A'')
and (36A'') or its pharmaceutically acceptable salt or a solvate thereof
wherein the composition has a P2X3 and/or P2X2/3 receptor
antagonistic effect.

[0258] (38A) The pharmaceutical composition according to (37A) which has a
P2X3 and/or P2X2/3 receptor antagonistic effect.

[0259] (39A) A compound according to any one of the above (20A) to (36A),
(35A'), (36A'), (35A'') and (36A''), or its pharmaceutically acceptable
salt or a solvate thereof for use in a method for treating and/or
preventing a disease related to P2X3 and/or P2X2/3 receptor.

[0260] (40A) A method for treating and/or preventing a disease related to
P2X3 and/or P2X2/3 receptor comprising administering the
compound according to (20A) to (36A), (35A'), (36A'), (35A''), (36A'')
and (36A'''), or its pharmaceutically acceptable salt or a solvate
thereof.

[0261] (41A) A compound according to any one of the above (20A) to (36A),
(35A'), (36A'), (35A''), (36A'') and (36A'''), or its pharmaceutically
acceptable salt or a solvate thereof for use in a method for treating
pain and/or urination disorder.

[0262] (42A) A method for relieving pain and/or treating urination
disorder comprising administering the compound according to (20A) to
(36A), (35A'), (36A'), (35A''), (36A'') and (36A''') or its
pharmaceutically acceptable salt or a solvate thereof.

Effect of the Invention

[0263] The compound of the invention has an antagonistic effect on
P2X3 and/or P2X2/3 receptor and is useful in the treatment of
diseases or conditions associated with a P2X3 and/or P2X2/3
receptor, especially chronic pain, overactive bladder, etc.

MODE FOR CARRYING OUT THE INVENTION

[0264] As used throughout the specification, the following terms have the
following meaning unless specifically indicated.

[0265] The term "halogen" means fluoro, chloro, bromo and iodo.

[0266] The halogen moiety in said "haloalkyl", "haloalkylcarbamoyl" and
"haloalkyloxy" is as defined above for "halogen".

[0267] The term "alkyl" includes a straight or branched chain monovalent
hydrocarbon group of a carbon number of 1 to 15, as one embodiment a
carbon number of 1 to 10, and as another embodiment a carbon number of 1
to 6. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl,
n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl,
n-decyl, n-undecanyl, dodecanyl, tridecanyl, and the like.

[0269] The term "alkyloxy" includes an alkyloxy group of which alkyl
moiety is as defined above for "alkyl". For example, methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc are exemplified as
alkyloxy.

[0270] The alkyloxy moiety in said "haloalkyloxy", "arylalkyloxy",
"alkyloxycarbonyl", "alkyloxycarbonylalkyl", and "alkyloxyimino" is as
defined above for "alkyloxy".

[0272] For example, methyloxycarbonyl, ethyloxycarbonyl,
n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl,
tert-butyloxycarbonyl, n-pentyloxycarbonyl, and the like are exemplified
as "alkyloxycarbonyl".

[0273] For example, mono- or di-alkylcarbamoyl, such as methylcarbamoyl,
ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl,
cyclopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl,
diethylcarbamoyl, dipropylcarbamoyl, and the like are exemplified as
"alkylcarbamoyl".

[0274] The term "alkenyl" includes linear or branched alkenyl of a carbon
number of 2 to 15, as one embodiment a carbon number of 2 to 10, and as
another embodiment a carbon number of 2 to 6 having one or more double
bonds at any available position. Examples include vinyl, propenyl,
isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl,
isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl,
octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl and the like.

[0275] The alkenyl moiety in said "alkenyloxy", "alkenylthio",
"alkenylcarbamoyl", "alkenylsulfamoyl" and "alkenyloxycarbonyl" is as
defined above for "alkenyl".

[0276] The term "alkynyl" includes a linear or branched alkynyl of a
carbon number of 2 to 15, as one embodiment a carbon number of 2 to 10,
as another embodiment a carbon number 2 to 6. Examples include ethynyl,
propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and
decynyl. These have one or more triple bonds at any available position
and may further a double bond.

[0277] The alkynyl moiety in said "alkynyloxy", "alkynylthio" and
"alkynyloxycarbonyl" is as defined above for "alkynyl".

[0278] The term "acyl" includes a group of the formula R--C(═O)--,
wherein R is, for example, "hydrogen", "alkyl", "alkenyl" or "alkynyl" as
defined above and "cycloalkyl", "cycloalkenyl", "non-aromatic
heterocyclic group", "aryl" or "heteroaryl" as defined below.

[0279] The acyl moiety in "acylamino" and "acylimino" is as defined above
for "acyl"

[0281] The term "cycloalkyl" includes a monovalent group derived from
"cycloalkane" as defined above. Monocyclic cycloalkyl includes, for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl, cyclodecyl, etc. As one embodiment, C3 to C8
cycloalkane is exemplified. As another embodiment, C3 to C7 cycloalkane
is exemplified. Polycyclic cycloalkyl includes norbornyl,
tetrahydronaphthalene 5-yl, tetrahydronaphthalene-6-yl, etc.

[0282] Examples of "cycloalkyl" for R2 are cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl and the like.

[0283] Examples of "cycloalkyl" for R3 are cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl and the like.

[0284] The cycloalkyl moiety in said "cycloalkyloxycarbonyl" and
"cycloalkyloxy" is as defined above for "cycloalkyl".

[0285] The term "cycloalkene" includes a non-aromatic monocyclic or
polycyclic ring of 3 to 10 carbons containing at least one carbon-carbon
double bond. As one embodiment C3 to C8 cycloalkene is exemplified. As
another embodiment C3 to C7 cycloalkene is exemplified. Monocyclic
cycloalkene includes, for example, cyclopentene, cyclohexene, etc.
Polycyclic cycloalkene includes norbornene, indene, etc.

[0286] The term "cycloalkenyl" includes a monovalent group derived from
"cycloalkene" as defined above. Monocyclic cycloalkenyl includes
cyclopentenyl, cyclohexenyl, etc. As one embodiment, C3 to C8 cycloalkane
is exemplified. As another embodiment, C3 to C7 cycloalkane is
exemplified. Polycyclic cycloalkenyl includes norbornenyl, indene-1-yl,
indene-2-yl, indene-3-yl, etc.

[0287] The cycloalkenyl moiety in said "cycloalkenyloxycarbonyl" and
"cyclolalkenyloxy" is as defined above for "cycloalkenyl".

[0288] The term "aromatic carbocyclic ring" includes an aromatic
hydrocarbocyclic ring which is monocyclic or fused-cyclic, such as
benzene ring, naphthalene ring, anthracene ring, phenanthrene ring, etc.

[0289] The term "aryl" includes a monovalent group derived from "aromatic
carbocyclic ring" as defined above. For example, phenyl, 1-naphthyl,
2-naphthyl, anthryl, phenanthryl, etc. are exemplified.

[0290] Preferable "aryl" for R3 is phenyl.

[0291] The aryl moiety in said "aryloxy", "arylthio" and "aryloxycarbonyl"
is as defined above for "aryl".

[0292] The term "heterocyclic ring" includes an aromatic or a non-aromatic
monocyclic or fused-cyclic ring, which includes a five- to seven-membered
ring having at least one nitrogen atom, oxygen atom, and/or sulfur atom
in the ring;

a fused ring consisting of two or more said five- to seven-membered
rings; or a fused ring consisting of said five- to seven-membered ring
having at least one nitrogen atom, oxygen atom, and/or sulfur atom in the
ring fused to one or more "aromatic carbocyclic ring", "cycloalkane" or
"cycloalkene" as defined above.

[0300] The term "non-aromatic carbocyclic ring" includes "cycloalkane" as
defined above, "cycloalkene" as defined above, a fused ring consisting of
"aromatic carbocyclic ring" as defined above fused to "cycloalkane" or
"cycloalkene" as defined above. As a fused ring, indene and the like are
exemplified.

[0302] The non-aromatic carbocyclyl moiety in said "non-aromatic
carbocyclyloxy" and "non-aromatic carbocyclylalkyloxy" is as defined
above for "non-aromatic carbocyclic ring".

[0303] The term "aromatic heterocyclic ring" includes aromatic rings of
"heterocyclic ring" as defined above.

[0304] "Aromatic heterocyclic ring" includes a five- to seven-membered
aromatic ring having at least one nitrogen atom, oxygen atom, and/or
sulfur atom in the ring;

a fused aromatic ring consisting of two or more said rings; and a fused
ring consisting of a five- to seven-membered aromatic ring having at
least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring
fused to one or more "aromatic carbocyclic ring" as defined above.

[0310] The term "heteroaryl" includes a monovalent group derived from
"aromatic heterocyclic ring" as defined above. "Heteroaryl" includes a
five- to seven-membered aromatic group having at least one nitrogen atom,
oxygen atom, and/or sulfur atom in the ring;

a fused aromatic group consisting of two or more said rings; and a fused
ring consisting of a five- to seven-membered aromatic group having at
least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring
fused to one or more "aromatic carbocyclic ring" as defined above.

a fused non-aromatic ring consisting of two or more said rings: a fused
ring consisting of a five- to seven-membered aromatic ring having at
least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring
fused to one or more "cycloalkane" or "cycloalkene" as defined above; and
a fused ring consisting of a five- to seven-membered non-aromatic
heterocyclic ring having at least one nitrogen atom, oxygen atom, and/or
sulfur atom in the ring fused to one or more "aromatic carbocyclic ring"
or "non-aromatic carbocyclic ring" as defined above.

[0323] a fused heterocyclic group such as benzodioxane,
tetrahydroquinoline, benzo[d]oxazole-2(3H)-one, tetrahydrobenzothiophene
etc.

[0324] The non-aromatic heterocyclyl moiety in said "non-aromatic
heterocyclyloxy" and "non-aromatic heterocyclyloxycarbonyl" is as defined
above for "non-aromatic heterocyclic ring".

[0325] The term "nitrogen-containing non-aromatic heterocyclic group"
includes a group derived from a four- to seven-membered non-aromatic ring
which contains at least one nitrogen atom in the ring and may contain one
or more atoms arbitrarily selected from an oxygen atom and an sulfur atom
in the ring and a fused ring consisting of two or more said rings.
Examples are pyrrolinyl, pyrrolidino, pyrrolidinyl, piperidino,
piperidyl, piperazino, piperazinyl, morpholinyl, morpholino,
thiomorpholino etc.

[0326] The non-aromatic heterocyclyl moiety in said "non-aromatic
heterocyclyloxycarbonyl" is as defined above for "non-aromatic
heterocyclic ring".

[0327] Substituents for "substituted alkyl", "substituted alkenyl",
"substituted alkynyl", "substituted alkyloxy", "substituted alkenyloxy",
"substituted alkynyloxy", "substituted alkylthio", "substituted
alkenylthio", "substituted alkynylthio", "substituted alkyloxycarbonyl",
"substituted alkenyloxycarbonyl" and "substituted alkynyloxycarbonyl"
include but are not limited to one or more same or different substituents
selected from the group consisting of:

[0333] Substituents for "substituted carbamoyl", "substituted
thiocarbamoyl" and "substituted sulfamoyl" are one or more same or
different groups selected from, but are not limited to, the group
consisting of:

[0349] As substituents for "substituted aryl" and "substituted heteroaryl"
for R3, unsubstituted heteroaryloxyl, heteroaryloxyl substituted
with one or more same or different substituents selected from the above
Substituent Group Z and the like are exemplified. Further, halogen,
hydroxy, carboxy, cyano, nitro, alkyl, haloalkyl, haloalkyloxy, alkyloxy,
amino and the like are exemplified. The above heteroaryloxyl includes the
following groups which are unsubstituted or substituted with one or more
same or different substituents selected from the above Substituent Group
Z:

[0359] In general formula (VIII), general formula (IX), general formula
(VII), general formula (IV), general formula (I), general formula (II) or
general formula (III), "R4a and R4b attached to the same carbon
atom are taken together to form oxo or thioxo" includes the followings:

##STR00055##

wherein n, R4a, R4b, and R2 are as defined in the above
(1) and the like.

[0360] In general formula (VIII), the positions of carbon atom a, Qa
atom, Qb atom, carbon atom b, Qc atom and Qd atom which
constitute a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine
ring or a pyridazine ring as ring D is defined as 1-position, 2-position,
3-position, 4-position, 5-position and 6-position, respectively. Each of
the position numbers of these atoms is different from position number
based on IUPAC nomenclature. That is, "carbon atom a is positioned on
ring D in a 1,4 relationship with respect to carbon atom b" includes the
followings:

[0362] In general formula (VIII), the positions of carbon atom a, Qa
atom, Qb atom, carbon atom b, Qc atom and Qd atom which
constitute a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine
ring or a pyridazine ring as ring D is defined as 1-position, 2-position,
3-position, 4-position, 5-position and 6-position, respectively. Each of
the position numbers of these atoms is different from position number
based on IUPAC nomenclature. That is, "carbon atom a is positioned on
ring D in a 1,3 relationship with respect to carbon atom b" includes the
followings:

[0364] In general formula (IX), the positions of carbon atom a, Qa
atom, Qb atom, carbon atom b, Qc atom and Qd atom which
constitute a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine
ring or a pyridazine ring as ring D is defined as 1-position, 2-position,
3-position, 4-position, 5-position and 6-position, respectively. Each of
the position numbers of these atoms is different from position number
based on IUPAC nomenclature. That is, "carbon atom a is positioned on
ring D in a 1,4 relationship with respect to carbon atom b" includes the
followings:

[0366] In general formula (IX), each of the position of carbon atom a,
Qa atom, Qb atom, carbon atom b, Qc atom and Qd atom
which constitute a benzene ring, a pyridine ring, a pyrimidine ring, a
pyrazine ring or a pyridazine ring as ring D is defined as 1-position,
2-position, 3-position, 4-position, 5-position and 6-position,
respectively. Each of the position numbers of these atoms is different
from position number based on IUPAC nomenclature. That is, "carbon atom a
is positioned on ring D in a 1,3 relationship with respect to carbon atom
b" includes the followings:

[0368] In general formula (VIII), general formula (IX), and general
formula (VII), "R11a and R11b together with the carbon atom to
which they are attached form a substituted or unsubstituted cycloalkane
ring, a substituted or unsubstituted cycloalkene ring, or a substituted
or unsubstituted non-aromatic heterocyclic ring" includes the followings:

##STR00056##

wherein m, R11a and R11b are as defined in the above (21); v is
an integer of 0 to 3 (e.g., 0 or 1, and e.g., 0);

--W-- is --O--, --S-- or --N(R17)-- (e.g., --O--);

[0369] R17 is a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted acyl and the like.

[0370] In general formula (VIII), general formula (IX), and general
formula (VII), "R14a and R14b together with the carbon atom to
which they are attached form a substituted or unsubstituted cycloalkane
ring, a substituted or unsubstituted cycloalkene ring, or a substituted
or unsubstituted non-aromatic heterocyclic ring" includes the followings:

##STR00057## ##STR00058##

wherein t, R14a and R14b are as defined in the above (24); va
is an integer of 0 to 3 (e.g., 0 or 1, and e.g., 0)

-Wa- is --O--, --S-- or --N(R17a)-- (e.g., --O--):

[0371] R17a is a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted acyl and the like.

[0372] In general formula (VIII), general formula (IX), and general
formula (VII), "R14a' and R14b' together with the carbon atom
to which they are attached form a substituted or unsubstituted
cycloalkane ring, a substituted or unsubstituted cycloalkene ring, or a
substituted or unsubstituted non-aromatic heterocyclic ring" includes the
followings:

##STR00059## ##STR00060## ##STR00061##

wherein t, R14a and R14b are as defined in the above (24); va
is an integer of 0 to 3 (e.g., 0 or 1, and e.g., 0);

-Wa- is --O--, --S-- or --N(R17a)-- (e.g., --O--);

[0373] R17a is a hydrogen atom, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted acyl and the like.

[0374] One embodiment of the compound of the present invention or the
composition of the present invention is mentioned below.

[0375] The following (II''-A) to (II''-C) are embodiments of a
pharmaceutical composition having an analgesic effect or and/or an
improving effect of urination disorder comprising the compound of the
formula (II''):

##STR00062##

or its pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

(II''-A)

[0376] A pharmaceutical composition having an analgesic effect and/or an
improving effect of urination disorder comprising the compound wherein
Rc1 is alkyl substituted with one or more substituents selected from
Substituent Group A (Substituent Group A: halogen, cyano, hydroxy,
carboxy, sulfo, substituted or unsubstituted alkyloxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, and substituted or unsubstituted
guanidyl), alkenyl substituted with one or more substituents selected
from Substituent Group A, or alkynyl substituted with one or more
substituents selected from Substituent Group A: R2 is aryl
optionally substituted with one or more substituents selected from
Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl,
alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl,
cycloalkynyl, and alkylsilylalkynyl), heteroaryl optionally substituted
with one or more substituents selected from Substituent Group C, or
cycloalkyl optionally substituted with one or more substituents selected
from Substituent Group C; R3 is aryl optionally substituted with one
or more substituents selected from Substituent Group D (Substituent Group
D: halogen: hydroxy; alkyl optionally substituted with halogen, hydroxy,
cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl;
alkenyl optionally substituted with cycloalkyl; alkynyl optionally
substituted with cycloalkyl; alkyloxy optionally substituted with
halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group
optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl
cycloalkyloxy: aryloxyl; heteroaryloxyl optionally substituted with
alkyl; a non-aromatic heterocyclic group; and alkylamino), heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group D; R4a and R4b are both hydrogen; R5 is
hydrogen, or its pharmaceutically acceptable salt or a solvate thereof as
an active ingredient.

(II''-B)

[0377] A pharmaceutical composition having an analgesic effect and/or an
improving effect of urination disorder comprising the compound wherein
Rc1 is a group of the formula:

##STR00063##

wherein t is an integer of 1 to 4; Rc2 is halogen, cyano, hydroxy,
carboxy, sulfo, substituted or unsubstituted alkyloxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl,
substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or
unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or
unsubstituted aryloxylcarbonyl, substituted or unsubstituted
heteroaryloxylcarbonyl, substituted or unsubstituted carbamoyl,
substituted or unsubstituted sulfamoyl, substituted or unsubstituted
amino, substituted or unsubstituted imino, substituted or unsubstituted
guanidyl, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkenylthio, substituted or unsubstituted alkynylthio,
substituted or unsubstituted acyl, substituted or unsubstituted
cycloalkyloxycarbonyl, substituted or unsubstituted
cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic
heterocyclyloxycarbonyl, substituted or unsubstituted aryloxylcarbonyl,
substituted or unsubstituted heteroaryloxylcarbonyl, or nitro; Rc3
and Rc4 are each independently hydrogen, hydroxy, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
or substituted or unsubstituted alkynyl, or (i) Rc3 and Rc4 are
taken together to form oxo or thioxo, or, (ii) Rc3 and Rc4
attached to the same carbon atom, are taken together to form
--(CRc5Rc6)x-; Rc5 and Rc6 are each independently
hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, or substituted or unsubstituted
alkynyl; R2 is substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or heteroaryl optionally substituted with one
or more substituents selected from Substituent Group C; x is an integer
of 1 to 4; R3 is aryl optionally substituted with one or more
substituents selected from Substituent Group D, or heteroaryl optionally
substituted with one or more substituents selected from Substituent Group
D: R4a and R4b are both hydrogen;

[0378] R5 is hydrogen.

its pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

(II''-C)

[0379] A pharmaceutical composition having an analgesic effect and/or an
improving effect of urination disorder comprising the compound of the
above (II''-A) wherein Rc1 is alkyl substituted with one or more
substituents selected from Substituent Group E (Substituent Group E:
sulfo; substituted or unsubstituted sulfamoyl; substituted or
unsubstituted imino; substituted or unsubstituted guanidyl; a substituted
or unsubstituted non-aromatic heterocyclic group (provided that the
heterocyclic group is morpholino, imidazolidine, tetrahydropyranyl and
piperizino) and substituted or unsubstituted heteroaryl (provided that
the heteroaryl is pyridino)), alkenyl optionally substituted with one or
more substituents selected from Substituent Group E, or alkynyl
substituted with one or more substituents selected from Substituent Group
E, or its pharmaceutically acceptable salt or a solvate thereof as an
active ingredient.

[0380] One embodiment of the compound of the present invention or the
composition of the present invention is mentioned below.

[0381] The following (III''-A) to (III''-C) are embodiments of a
pharmaceutical composition having an analgesic effect and/or an improving
effect of urination disorder comprising the compound of the formula
(III''):

##STR00064##

or its pharmaceutically acceptable salt or a solvate thereof as an active
ingredient.

(III'-A)

[0382] A pharmaceutical composition having an analgesic effect and/or an
improving effect of urination disorder comprising the compound wherein
Ra1 is alkyl substituted with one or more substituents selected from
Substituent Group A (Substituent Group A: halogen, cyano, hydroxy,
carboxy, sulfo, substituted or unsubstituted alkyloxy, substituted or
unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,
substituted or unsubstituted cycloalkyl, substituted or unsubstituted
cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic
group, substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxy
carbonyl, substituted or unsubstituted carbamoyl, substituted or
unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted
or unsubstituted imino, and substituted or unsubstituted guanidyl),
alkenyl substituted with one or more substituents selected from
Substituent Group A, alkynyl substituted with one or more substituents
selected from Substituent Group A, alkyloxy substituted with one or more
substituents selected from Substituent Group A, alkenyloxy substituted
with one or more substituents selected from Substituent Group A,
alkynyloxy substituted with one or more substituents selected from
Substituent Group A, alkylthio substituted with one or more substituents
selected from Substituent Group A, alkenylthio substituted with one or
more substituents selected from Substituent Group A, alkynylthio
substituted with one or more substituents selected from Substituent Group
A, alkylamino substituted with one or more substituents selected from
Substituent Group A, alkenylamino substituted with one or more
substituents selected from Substituent Group A or alknynylamino
substituted with one or more substituents selected from Substituent Group
A,

R2 is aryl optionally substituted with one or more substituents
selected from Substituent Group C (Substituent Group C: halogen, alkyl,
alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl,
cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl) or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group C; R3 is aryl optionally substituted with one or
more substituents selected from Substituent Group D (Substituent Group D:
halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy,
cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl;
alkenyl optionally substituted with cycloalkyl; alkynyl optionally
substituted with cycloalkyl; alkyloxy optionally substituted with
halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group
optionally substituted with alkyl: alkylthio; cycloalkyl; cycloalkenyl;
cycloalkyloxy; aryloxyl; heteroaryloxyl optionally substituted with
alkyl; a non-aromatic heterocyclic group; and alkylamino), or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group D: R4a and R4b are both hydrogen: R5 is
hydrogen, or its pharmaceutically acceptable salt or a solvate thereof as
an active ingredient.

(III'-B)

[0383] A pharmaceutical composition having an analgesic effect and/or an
improving effect of urination disorder comprising the compound wherein
Ra1 is

##STR00065##

wherein --Y-- is --O--, --S-- or --NRY--: RY is hydrogen,
substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
and other symbols are as defined in the above II'-B; Rc5 and
Rc6 are each independently, hydrogen, halogen, hydroxy, substituted
or unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl; R2 is substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl; x is an
integer of 1 to 4; R3 is aryl optionally substituted with one or
more substituents selected from Substituent Group D, or heteroaryl
optionally substituted with one or more substituents selected from
Substituent Group D; R4a and R4b are both hydrogen: R5 is
hydrogen, or its pharmaceutically acceptable salt or a solvate thereof as
an active ingredient.

[0384] One embodiment of the compound of the present invention is
mentioned below. A compound of the formula (VII'):

##STR00066##

wherein Rc1 is unsubstituted alkyl, alkyl substituted with one or
more substituents selected from Substituent Group A (Substituent Group A:
halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted
alkyloxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and substituted or unsubstituted guanidyl), unsubstituted alkenyl,
alkenyl substituted with one or more substituents selected from
Substituent Group A, unsubstituted alkynyl or alkynyl substituted with
one or more substituents selected from Substituent Group A; R4a and
R4b are both hydrogen; R2 is aryl optionally substituted with
one or more substituents selected from Substituent Group C (Substituent
Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyl
oxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl),
heteroaryl optionally substituted with one or more substituents selected
from Substituent Group C, or cycloalkyl optionally substituted with one
or more substituents selected from Substituent Group C; R5 is
hydrogen; R9 is halogen, hydroxy, carboxy, cyano, alkyloxy,
unsubstituted alkyl, alkyl optionally substituted with one or more
substituents selected from Substituent Group F (Substituent Group F:
halogen, hydroxy, carboxy, cyano, alkyloxyimino, dialkylamino, alkyloxy,
cycloalkyl, and heteroaryl), unsubstituted alkenyl, alkenyl optionally
substituted with one or more substituents selected from Substituent Group
F, unsubstituted alkynyl, or alkynyl optionally substituted with one or
more substituents selected from Substituent Group F; and s is an integer
of o to 2, its pharmaceutically acceptable salt or a solvate thereof.

[0385] One embodiment of the compound of the present invention is
mentioned below. A compound of the formula (VIII'):

##STR00067##

wherein Rc1 is unsubstituted alkyl, alkyl substituted with one or
more substituents selected from Substituent Group A (Substituent Group A:
halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted
alkyloxy, substituted or unsubstituted alkenyloxy, substituted or
unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or unsubstituted
alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,
substituted or unsubstituted alkynyloxycarbonyl, substituted or
unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted amino, substituted or unsubstituted imino,
and substituted or unsubstituted guanidyl), unsubstituted alkenyl,
alkenyl substituted with one or more substituents selected from
Substituent Group A, unsubstituted alkynyl or alkynyl substituted with
one or more substituents selected from Substituent Group A; R4a and
R4b are both hydrogen; R2 is aryl optionally substituted with
one or more substituents selected from Substituent Group C (Substituent
Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy,
alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and
alkylsilylalkynyl), heteroaryl optionally substituted with one or more
substituents selected from Substituent Group C, or cycloalkyl optionally
substituted with one or more substituents selected from Substituent Group
C; R5 is hydrogen;

[0387] The following embodiments are examples of the compound (VIII) of
the present invention.

[0388] A compound of the formula (VIII-a):

##STR00068##

wherein Rc is selected from the following (a1) to (a32):

##STR00069## ##STR00070## ##STR00071##

wherein R15a, R15b, R15a' and R15b' are each
independently selected from the following (b1) and (b2): (b1) a hydrogen
atom, cyano, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl,
substituted or unsubstituted acyl, substituted sulfonyl or substituted
sulfinyl, and (b2) a hydrogen atom, methyl, ethyl, acetyl or
trifluoroacetyl. (a31) ethyl; and (a32) methyl; ring F is selected from
the following (c1) to (c3) (c1) a benzene ring; (c2) a pyridine ring; and
(c3) a cyclohexane ring; R30 is selected from the following (d1) and
(d2): (d1) halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl or substituted or unsubstituted alkynyl; and (d2)
fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl
or ethyl; R31 is halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl or substituted or unsubstituted
alkynyl; n'' is 0 or 1; ring D is selected from the following (e1) and
(e2): (e1) a benzene ring; and (e2) a pyridine ring; relationship of
carbon atom a and carbon atom b on the ring D are selected from the
following (f1) and (f2): (f1) 1,4 relationship; and (f2) 1,3
relationship; ring B is selected from the following (g1) to (g12): (g1) a
thiazole ring; (g2) an isothiazole ring; (g3) an oxazole ring; (g4) an
isoxazole ring; (g5) a thiadiazole ring; (g6) an oxadiazole ring; (g7) a
pyridine ring; (g8) a pyrimidine ring; (g9) a pyrazine ring; (g10) a
pyridazine ring; (g11) a triazine ring; and (g12) a pyrazole ring; s' is
selected from the following (h1) and (h2): (h1) 0; and (h2) 1; when s' is
1, then R9' is selected from the following (i1) to (i14): (i1)
hydroxy; (i2) carboxy; (i3) cyano; (i4) alkyl substituted with hydroxy,
carboxy, cyano, carbamoyl, amino, sulfamoyl, methanesulfonyl or
methanesulfinyl; (i5) substituted or unsubstituted carbamoyl; (i6)
alkylcarbamoyl or alkenylcarbamoyl; (i7) substituted or unsubstituted
amino; (i8) amino substituted with carbamoyl, alkylcarbamoyl,
alkylcarbamoylalkyl, carbamoylalkyl or carboxyalkyl; (i9) substituted or
unsubstituted sulfamoyl; (i10) alkylsulfamoyl or alkenylsulfamoyl; (i11)
substituted sulfonyl; (i12) substituted sulfinyl; (i13) unsubstituted
alkyl, or alkyl substituted with halogen, haloalkyloxy, cycloalkyl,
cycloalkenyl, alkyloxy or alkenyloxy; and (i14) unsubstituted alkyl.

[0389] The compound of the formula (VIII-a) of the present invention
includes the compounds comprising the combination of some or all of
options of the above (a1) to (a32), (b1) and (b2), (c1) to (c3), (d1) and
(d2), (e1) and (e2), (f1) and (f2), (g1) to (g12), (h1) and (h2), and
(i1) to (i14).

[0390] The following embodiments are examples of the compound (VIII) of
the present invention.

[0391] A compound of the formula (VIII-b):

[Chemical Formula 67]

[0392] wherein Rc is a group selected from the following (ba1) to
(ba16): (ba1) a group of the formula: --(CR11aR11b)m-OH wherein
R11a and R11b are each independently, a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
or substituted or unsubstituted alkynyl, or R11a and R11b
together with the carbon atom to which they are attached form a
substituted or unsubstituted cyclopropane ring, a substituted or
unsubstituted cyclopropene ring, a substituted or unsubstituted oxetane
ring, a substituted or unsubstituted thietane ring, or a substituted or
unsubstituted azetizine ring; m is an integer of 2 to 4; (ba2) a group of
the formula: --(CR11aR11b)m-OH] wherein R11a is a hydrogen
atom, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, or substituted or unsubstituted alkynyl; R11b is a group of
the formula: --(CR12aR12b)u-OH wherein R12a and R12b
are each independently a hydrogen atom, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, or substituted or
unsubstituted alkynyl; u is an integer of 0 to 2; m is an integer of 2 to
4; (ba3) a group of the formula:

##STR00072## ##STR00073##

(ba4) a group of the formula:

##STR00074##

(ba5) a group of the formula:

##STR00075##

(ba6) a group of the formula:
--(CR14aR14b)t-N(R15a)(R15b) wherein R14a and
R14b are each independently hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted
or unsubstituted alkynyl, or

[0393] R14a and R14b together with the carbon atom to which they
are attached form a substituted or unsubstituted cyclopropane ring, a
substituted or unsubstituted cyclopropene ring, a substituted or
unsubstituted oxetane ring, a substituted or unsubstituted thietane ring,
or a substituted or unsubstituted azetizine ring; t is an integer of 2 to
4; R15a and R15b are each independently a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbamoyl, substituted or unsubstituted sulfamoyl, substituted or
unsubstituted acyl, substituted sulfonyl or substituted sulfinyl;

(ba7) a group of the formula:

##STR00076##

wherein R15a and R15b are as defined in the above (ba6); (ba8)
a group of the formula:

##STR00077##

wherein R15a and R15b are as defined in the above (ba6); (ba9)
a group of the formula:
--(CR14a'R14b')t'-C(═O)N(R15a')(R15b') wherein
R14a' and R14b' are each independently a hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
or substituted or unsubstituted alkynyl, or R14a' and R14b'
together with the carbon atom to which they are attached form a
substituted or unsubstituted cyclopropane ring, a substituted or
unsubstituted cyclopropene ring, a substituted or unsubstituted oxetane
ring, a substituted or unsubstituted thietane ring, or a substituted or
unsubstituted azetizine ring; t' is an integer of 1 to 4; R14a' and
R15b' are each independently a hydrogen atom, cyano, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbamoyl,
substituted or unsubstituted sulfamoyl, substituted or unsubstituted
acyl, substituted sulfonyl or substituted sulfinyl: (ba10) a group of the
formula:

##STR00078##

wherein R15a' and R15b' are as defined in the above (ba9);
(ba11) a group of the formula:

##STR00079##

wherein R15a' and R15b' are as defined in the above (ba9);
(ba12) a group of the formula:

##STR00080##

wherein R15' and R15b' are as defined in the above (ba9):
(ba13) unsubstituted alkyl; or alkyl substituted with halogen,
haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; (ba14)
unsubstituted alkyl; (ba15) methyl; ethyl; methyl substituted with
halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy:
or ethyl substituted with halogen, haloalkyloxy, cycloalkyl,
cycloalkenyl, alkyloxy or alkenyloxy; and (ba16) methyl or ethyl; ring F
is a group selected from the following (bc1) and (bc2): (bc1) a benzene
ring, a pyridine ring or a cyclohexane ring; and (bc2) a benzene ring;
R30 is a group selected from the following (bd1) and (bd2): (bd1)
halogen, substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl or substituted or unsubstituted alkynyl; and (bd2) fluoro,
chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or
ethyl; R31 is halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl or substituted or unsubstituted
alkynyl; n'' is 0 or 1; ring D a group selected from the following (be1)
to (be4): (be1) a benzene ring, a pyridine ring, a pyrimidine ring, a
pyrazine ring or a pyridazine ring; (be2) a benzene ring or a pyridine
ring; (be3) a benzene ring; and (be4) a pyridine ring; relationship of
carbon atom a and carbon atom b on ring D is selected from the following
(bf1) to (bf3): (bf1) 1, 4 relationship or 1, 3 relationship; (bf2) 1, 4
relationship; and (bf3) 1, 3 relationship; ring B is a group selected
from the following (bg1) to (bg9): (bg1) an aromatic heterocyclic ring;
(bg2) a five- or six-membered aromatic heterocyclic ring; (bg3) a
thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a
thiadiazole ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring,
a pyrazine ring, a pyridazine ring, a triazine ring, or a pyrazole ring;
(bg4) a thiazole ring, an isoxazole ring, a thiadiazole ring, a pyridine
ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring; (bg5) a
six-membered aromatic heterocyclic ring; (bg6) a pyridine ring, a
pyrimidine ring, a pyrazine ring, a pyridazine ring or a triazine ring;
(bg7) a five-membered aromatic heterocyclic ring; (bg8) a thiazole ring,
an isothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazole
ring, an oxadiazole ring or a pyrazole ring; and (bg9) a thiazole ring,
an isoxazole ring or a thiadiazole ring; s' is a group selected from the
following (bh1) to (bh3): (bh1) 0 or 1; (bh2) 0; and (bh3) 1; when s' is
1, then R9' is a group selected from the following (bi1) to (bi7):
(bi1) hydroxy; carboxy; cyano; alkyl substituted with hydroxy, carboxy,
cyano, carbamoyl, amino, sulfamoyl, methanesulfonyl or methanesulfinyl;
substituted or unsubstituted carbamoyl; substituted or unsubstituted
amino; substituted or unsubstituted sulfamoyl; substituted sulfonyl; or
substituted sulfinyl; (bi2) hydroxy; carboxy; cyano; alkyl substituted
with hydroxy, carboxy, cyano, carbamoyl, amino, sulfamoyl,
methanesulfonyl or methansulfinyl; carbamoyl; alkylcarbamoyl; amino
substituted with alkyl, haloalkyl, hydroxy alkyl, alkyloxy, haloalkyloxy,
carbamoyl, alkylcarbamoyl, alkylcarbamoylalkyl, carbamoylalkyl or
carboxyalkyl; sulfamoyl; alkylsulfamoyl; alkylsulfonyl; or alkylsulfinyl;
(bi3) carboxy; carbamoyl; alkylcarbamoyl; sulfamoyl; alkylsulfamoyl or
alkylsulfonyl; (bi4) alkyl substituted with halogen, haloalkyloxy,
cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or unsubstituted alkyl;
(bi5) unsubstituted alkyl; (bi6) methyl; ethyl; methyl substituted with
halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy;
or ethyl substituted with halogen, haloalkyloxy, cycloalkyl,
cycloalkenyl, alkyloxy or alkenyloxy; and (bi7) methyl or ethyl, or its
pharmaceutically acceptable salt or a solvate thereof. The compound of
the formula (VIII-b) of the present invention includes the compounds
comprising the combination of some or all of options of the above (ba1)
to (ba16), (bc1) and (bc2), (bd1) and (bd2), (be1) to (be4), (bf1) to
(bf3), (bg1) to (bg9), (bh1) to (bh3) and (bi1) to (bi7).

[0394] The following embodiments are examples of the compound (IX) of the
present invention.

[0395] A compound of the formula (IX-a):

##STR00081##

wherein Rc is a group selected from the following (ca1) to (ca5): (ca1) a
group of the formula: --(CR11aR11b)m-OH wherein R11a and
R11b are each independently, a hydrogen atom, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted
or unsubstituted alkynyl, or R11a and R11b together with the
carbon atom to which they are attached form a substituted or
unsubstituted cyclopropane ring, a substituted or unsubstituted
cyclopropene ring, a substituted or unsubstituted oxetane ring, a
substituted or unsubstituted thietane ring, or a substituted or
unsubstituted azetizine ring: m is an integer or 2 to 4: (ca2) Rc is a
group of the formula: --(CR11aR11b)m-OH wherein R11a is a
hydrogen atom, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, or substituted or unsubstituted alkynyl;

[0396] R11b is a group of the formula; --(CR12aR12b)u-OH;

wherein R12a and R12b are each independently, hydrogen atom,
substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl,
or substituted or unsubstituted alkynyl; u is an integer of 0 to 2; m is
an integer of 2 to 4; (ca3) a group of the formula:

##STR00082## ##STR00083##

(ca4) a group of the formula:

##STR00084##

and (ca5) a group of the formula:

##STR00085##

ring F is a group selected from the following (cc1) and (cc2): (cc1) a
benzene ring, a pyridine ring or a cyclohexane ring; and (cc2) a benzene
ring; R30 is a group selected from the following (cd1) and (cd2):
(cd1) halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl or substituted or unsubstituted alkynyl; and (cd2)
fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl
or ethyl; R31 is halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl or substituted or unsubstituted
alkynyl; n'' is 0 or 1; ring D is a group selected from the following
(ce1) to (ce4): (ce1) a benzene ring, a pyridine ring, a pyrimidine ring,
a pyrazine ring or a pyridazine ring; (ce2) a benzene ring or a pyridine
ring; (ce3) a benzene ring; and (ce4) a pyridine ring; relationship of
carbon atom a and carbon atom b on ring D is selected from the following
(cf1) to (cf3): (cf1) 1,4 relationship, or 1,3 relationship; (cf2) 1,4
relationship; and (cf3) 1,3 relationship; ring E is a group selected from
the following (cg1) to (cg3): (cg1) a cycloalkane ring or a cycloalkene
ring: (cg2) a cycloalkane ring; and (cg3) a cyclopropane ring; s' is
(ch1) 0 or 1; (ch2) 0; and (ch3) 1; when s' is 1, then R9' is a
group selected from the following (ci1) to (ci4): (ci1) alkyl substituted
with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or
alkenyloxy; or unsubstituted alkyl; (ci2) unsubstituted alkyl; (ci3)
methyl: ethyl; methyl substituted with halogen, haloalkyloxy, cycloalkyl,
cycloalkenyl, alkyloxy or alkenyloxy; or ethyl substituted with halogen,
haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; and (ci4)
methyl or ethyl, or its pharmaceutically acceptable salt or a solvate
thereof.

[0397] The compound of the formula (VIII-b) of the present invention
includes the compounds comprising the combination of some or all of
options of the above (ca1) to (ca5), (cc1) and (cc2), (cd1) and (cd2),
(ce1) to (ce4), (cf1) to (cf3), (cg1) to (cg3), (ch1) to (ch3) and (ci1)
to (ci4).

[0398] The following embodiments are examples of the compound (VIII) of
the present invention.

[0401] The following embodiments are examples of the compound (IX) of the
present invention.

[0402] A compound of the formula (IX-b):

[Chemical Formula 84]

[0403] wherein Hal is halogen;

Rc is

[0404] (ea1) a group of the formula:

##STR00091## ##STR00092##

(ea2) a group of the formula:

##STR00093##

(ea3) a group of the formula:

##STR00094##

ring E is (eg1) a cycloalkane ring or a cycloalkene ring; (eg2) a
cycloalkane ring; (eg3) a cyclopropane ring; a group of the formula:
(R9')s'- is (ej1) s' is 0; (ej2) s' is 1, and R9' is alkyl
substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl,
alkyloxy or alkenyloxy; or unsubstituted alkyl; (ej3) s' is 1, and
R9' is unsubstituted alkyl; (ej4) s' is 1, and R9' is methyl;
ethyl; methyl substituted with halogen, haloalkyloxy, cycloalkyl,
cycloalkenyl, alkyloxy or alkenyloxy; or ethyl substituted with halogen,
haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or (ej5)
s' is 1, and R9' is methyl or ethyl, or its pharmaceutically
acceptable salt or a solvate thereof.

[0405] The compound of the formula (IX-b) of the present invention
includes the compounds comprising the combination of some or all of
options of the above. Specifically, the following combinations are
included.

[0406] The following is a general method for synthesizing the compounds of
this invention. The starting materials and reagents used for synthesizing
these compounds are commercially available or can be manufactured in
accordance with a widely known method in this field using commercially
available compounds.

[0407] For example, the compounds of the general formula (I), general
formula (II), general formula (III), general formula (IV), general
formula (VII), general formula (VIII) and general formula (IX) described
in this invention can be manufactured by the following synthesis route:

[Method A]

##STR00095##

[0408] wherein, Lg is a leaving group of the formula:

##STR00096##

R10 is alkyl, R27 is alkyl, n' is an integer from 0 to 3,
Lg1 is a leaving group and other symbols are as defined above.

(Step 1)

[0409] The compound (i) or its hydrochloride or bromate is reacted with
isocyanate (ii) or 1-carbamoyl imidazole (ii)' in a solvent, such as
N,N-dimethylformamide, N,N-dimethylacetamide, N,N'-dimethyl
imidazolidinone and dimethylsulfoxide, in the presence of a base, such as
DBU, triethylamine and pyridine (preferably DBU) at a temperature between
-20 and 50° C., preferably at a temperature between -10° C.
and below zero. After that, the compound (iii) can be manufactured by
reacting the reactive mixture with a carbonylating or thiocarbonylating
agent, such as 1,1'-carbonyldiimidazole, 1,1'-thiocarbonyldiimidazole,
phosgene, thiophosgene and triphosgene, etc., and a base, such as DBU,
triethylamine or pyridine (preferably DBU) at a temperature between -20
and 50° C., preferably at a temperature between -10° C. and
below zero.

(Step 2)

[0410] The compound (v) can be manufactured by reacting the compound (iii)
with the compound (iv) in a solvent, such as acetonitrile, acetone, DMF
and DMSO, in the presence of a base, such as potassium carbonate and
sodium carbonate, at a temperature between 50° C. to reflux,
preferably at reflux.

[0411] The examples of leaving group include halogen and --OSO2
(CtF2t+1) wherein t is an integer from 1 to 4. As halogen,
chloro, iodo and bromo are preferred. As --OSO2(CtF2t+1)
group, --OTf group (trifluoromethanesulfonate) is preferred. This leaving
group can also be used in the aforementioned (60').

[0412] The base and/or carbonylating agent or thiocarbonylating agent in
(Step 1) and (Step 2) can also be used in the aforementioned (60').

[0413] The "carbonylating agent" and "thiocarbonylating agent" include a
reagent that is used in a reaction where --C(═O) or --C(═S)-- is
inserted.

(Step 3)

[0414] The compound indicated by the general formula (II) can be
manufactured by reacting the compound (v) with the compound (vii) in a
solvent, such as NMP, DMF and DMSO, or under solvent-free conditions
under microwave irradiation at a temperature between 150° C. and
250° C. preferably at a temperature between 200° C. and
230° C., or in a solvent, such as t-butanol, in the presence of an
acid, such as acetic acid, at a temperature between 60° C. and
150° C., preferably at a temperature between 80° C. and
120° C.

[0416] wherein Hal2 and Hal3 are halogen and other symbols are
as defined above.

(Step 1)

[0417] The compound (ix) can be manufactured by reacting the compound
(vii) with alkylating agent (viii), such as methyl iodide and ethyl
iodide, in a solvent, such as methanol and ethanol, at a temperature
between -40 and 30° C., preferably below zero.

(Step 2)

[0418] The compound (x) can be manufactured by reacting the compound (ix)
with isocyanate, such as N-(chlorocarbonyl)isocyanate, in a solvent, such
as dichloromethane, chloroform, 1,2-dichloroethane, in the presence of a
base, such as triethylamine and N,N-diisopropylethylamine, at a
temperature between -20 and 30° C., preferably below zero.

(Step 3)

[0419] The compound (xi) can be manufactured by reacting the compound (x)
with the compound (vi) in a solvent, such as t-butanol, isopropanol,
ethanol and acetonitrile, in the presence of an acid, such as acetic
acid, formic acid and methanesulfonic acid, at reflux.

(Step 4)

[0420] The compound indicated by the general formula (II) can be
manufactured by reacting the compound (xi) with the compound (xii) in a
solvent, such as DMF and NMP, in the presence of a base, such as
potassium t-butoxide and sodium hydride, at a temperature between 40 and
100° C., preferably at a temperature between 50 and 70° C.

[0422] wherein Pg1 is an appropriate hydroxy protecting group, s is
an integer from 1 to 4 and other symbols are as defined above.

(Step 1)

[0423] The compound (xiii) can be manufactured by reacting a mixture of
the compound (x) obtained by the method B, the alcohol (xii) whose one
hydroxyl group is protected, such as
2-(tetrahydro-2H-pyran-2-yloxy)ethanol and a solvent, such as THF and
dioxane, etc., with triphenylphosphine, and diethyl azodicarboxylate,
etc.

(Step 2)

[0424] The compound (xiv) can be manufactured by reacting the compound
(xiii) with the compound (vi) in the presence of an acid, such as formic
acid and acetic acid, etc., at reflux.

[Method D]

##STR00099##

[0425] wherein Pg2 is an appropriate amino protecting group. R11
is substituted or unsubstituted alkyl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
substituted or unsubstituted acyl, a substituted or unsubstituted
non-aromatic heterocyclic group, substituted or unsubstituted aryl or
substituted or unsubstituted heteroaryl, R12 is hydroxy or halogen,
t is an integer from 1 to 4 and other symbols are as defined above.)

(Step 1)

[0426] The compound (xvi) can be manufactured by reacting the compound
(xv) obtained by the method A or B with acid, such as hydrochloric
acid-dioxane solution, hydrochloric acid-methanol, hydrochloric
acid-ethyl acetate solution and trifluoroacetic acid, etc.

(Step 2)

[0427] The compound (xviii) can be manufactured by reacting the compound
(xvi) with the acid halide (xvii) (R12 is halogen) in a solvent,
such as THF and dioxane, etc., in the presence of a base, such as
triethylamine and diisopropylethylamine, etc. If necessary,
dimethylaminopyridine, etc., can be added.

[0428] Alternatively, the compound (xviii) can be manufactured by reacting
the compound (xvi) with the carboxylic acid (xvii, R12 is hydroxy)
in a solvent, such as THF and DMF, in the presence of a condensing agent,
such as 1-hydroxybenzotriazole and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and a base,
such as triethylamine and diisipropylethylamine, etc.

[Method E]

##STR00100##

[0429] wherein R13 is substituted or unsubstituted alkyl, R20a
and R20b are hydrogen, halogen, cyano, hydroxy, carboxy, sulfo,
substituted or unsubstituted alkyloxy, substituted or unsubstituted
alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted alkyloxycarbonyl, substituted or
unsubstituted alkenyloxycarbonyl, substituted or unsubstituted
alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted
or unsubstituted sulfamoyl, substituted or unsubstituted amino,
substituted or unsubstituted imino, substituted or unsubstituted guanidyl
or R20a and R20b are taken together to form oxo or thioxo, u is
an integer from 1 to 4, and other symbols are as defined above.

(Step 1)

[0430] The compound (xx) can be manufactured by reacting the compound (x)
obtained by the method B with the compound (xix) in a solvent, such as
DMF, NMP and THF, in the presence of a base, such as DBU, potassium
t-butoxide and sodium hydride, at a temperature between 0 and 80°
C., preferably at a temperature between 30 and 50° C.

(Step 2)

[0431] The compound (xxi) can be manufactured by reacting the compound
(xx) with the compound (vi) in a solvent, such as t-butanol, isopropanol,
ethanol and acetonitrile, in the presence of an acid such as formic acid,
acetic acid and methanesulfonic acid, etc., at reflux.

(Step 3)

[0432] The compound (xxii) can be manufactured by reacting the compound
(xxi) with a solution, such as lithium hydroxide aqueous solution, sodium
hydroxide aqueous solution and potassium hydroxide aqueous solution, in a
solvent, such as methanol and ethanol, or in a mixture of such solvent
and a solvent, such as THF and dioxane, etc.

[Method F]

##STR00101##

[0433] wherein R14 is substituted or unsubstituted alkyl, R15
and R16 are each independently substituted or unsubstituted alkyl,
substituted or unsubstituted arylalkyl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkenyl, substituted or unsubstituted
acyl, a substituted or unsubstituted non-aromatic heterocyclic group,
substituted or unsubstituted aryl or substituted or unsubstituted
heteroaryl, u is an integer from 1 to 4 and other symbols are as defined
above.

(Step 1)

[0434] The compound (xxiv) can be manufactured by reacting the compound
(xxiii) obtained by the method A or B with a solution, such as lithium
hydroxide aqueous solution, sodium hydroxide aqueous solution and
potassium hydroxide aqueous solution, in a solvent, such as methanol and
ethanol, or in a mixture of such solvent and a solvent, such as dioxane
and THF, etc.

(Step 2)

[0435] The compound (xxvi) can be manufactured by reacting the compound
(xxiv) with the compound (xxv) in a solvent, such as THF, DMF and NMP, in
the presence of a condensing agent, such as 1-hydroxybenzotriazole, HOAt,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, HATU and
PyBOP, and a base, such as triethylamine and diisipropylethylamine, etc.

[Method G]

##STR00102##

[0436] wherein Pg1 is an appropriate hydroxy protecting group and
other symbols are as defined above.

(Step 1)

[0437] The compound (xxvii) can be manufactured by reacting the compound
(xi) obtained by the method B with a halogenating agent, such as
phosphorous oxychloride and phosphorous oxybromide, under solvent-free
conditions or in a solvent, such as toluene and tetrahydrofuran, at a
temperature between 0 and 100° C., preferably at a temperature
between 40 and 60° C.

(Step 2)

[0438] The compound (xxviii) can be manufactured by reacting a mixture of
the alcohol (xv) whose one hydroxyl group is protected, such as
2-(tetrahydro-2H-pyran-2-yloxy)ethanol, and a solvent, such as THF,
dioxane and DMF, with the compound (xv) after adding a base, such as
sodium hydride and potassium t-butoxide.

(Step 3)

[0439] The compound (xxix) can be manufactured by reacting the compound
(xxviii) with an acid, such as hydrochloric acid, p-toluenesulfonic acid
or its hydrate and pyridine p-toluenesulfonate, in a solvent, such as
methanol, etc.

[Method H]

##STR00103##

[0440] wherein R21 is substituted or unsubstituted alkyl, substituted
or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkenyl, substituted or unsubstituted acyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl,
R22 is hydrogen, substituted or unsubstituted alkyl or substituted
or unsubstituted acyl, and other symbols are as defined above.

(Step 1)

[0441] The compound (xxxi) can be manufactured by reacting the compound
(xxvii) obtained by the method G with the compound (xxx) in a solvent,
such as THF and dioxane, etc.

[Method I]

##STR00104##

[0442] wherein the symbols in the formula are as defined above.

(Step 1)

[0443] The compound (xxxiii) can be manufactured by reacting the compound
(xxvii) obtained by the method G with the compound (xxxii) in a solvent,
such as THF and dioxane, after adding a base, such as sodium hydride,
etc.

[Method J]

##STR00105##

[0444] wherein R18 is substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl or substituted or unsubstituted alkynyl, Q is
dihydroxyboran, dialkoxyboran or dialkylboran,

##STR00106##

and other symbols are as defined above.

[0445] The compound (xxxiv) can be manufactured by reacting the compound
(xxvii) obtained by the method G with the compound (xxxiii) in a solvent,
such as THF and dioxane, in the presence of a palladium catalyst, and a
solution, such as potassium carbonate, cesium carbonate and sodium
carbonate aqueous solution, etc., at a temperature between 50° C.
and reflux, preferably at reflux, or under microwave irradiation at a
temperature of 120 and 200° C., preferably at a temperature
between 130 and 150° C.

[Method K]

##STR00107##

[0446] wherein R19 is substituted or unsubstituted alkyl, v is an
integer from 0 to 4 and other symbols are as defined above.

[0447] The compound (xxxvi) can be manufactured by hydrolyzing the
compound (xxxv) using a mixture of an ethers solvent, such as dioxane.
THF and DME, etc., an alcohols solvent, such as ethanol and methanol, or
a solvent, such as DMF, DMA. DMSO and NMP, and water, as well as using a
base, such as sodium hydroxide and lithium hydroxide. Although the
preferable reaction temperature is room temperature, it can be increased
if the reaction proceeds slowly.

(Step 2)

[0448] The compound (xxxvii) can be obtained by dissolving the compound
(xxxvi) in an alcohols solvent, such as methanol and ethanol, and
performing catalytic reduction using a hydrogenation reactor (such as
H-Cube [10% Pt--C, H2=1 atm]) or a metallic catalyst, such as
palladium-carbon, platinum oxide and chlorotris (triphenylphosphine)
rodiumu (I), etc.

[Method L]

##STR00108##

[0449] wherein the symbols in the formula are as defined above.

(Step 1)

[0450] The compound (ixl) can be manufactured by reacting a mixture of the
compound (x) obtained by the method B, the alcohol (xxxviii) and a
solvent, such as THF and dioxane, with triphenylphosphine, etc., and
diethyl azodicarboxylate, etc.

(Step 2)

[0451] The compound (II) can be manufactured by reacting the compound
(ixl) with the compound (vi) in the presence of an acid, such as formic
acid and acetic acid, at reflux.

[0452] Using the optically-active alcohol (xxxviii) enables to synthesize
the optically-active compound (II).

[0453] The alcohol used as an intermediate (xxxviii) is commercially
available or can be manufactured according to a method specified in the
following documents:

[0466] wherein R21 is hydrogen, substituted or unsubstituted alkyl or
substituted or unsubstituted alkoxy, etc., R22 is bromo or iodo,
R23 and R24 are each independently substituted or unsubstituted
alkyl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, a
substituted or unsubstituted non-aromatic heterocyclic group, substituted
or unsubstituted aryl or substituted or unsubstituted heteroaryl, and
other symbols are as defined above.

(Step 1)

[0467] The compound (xxxix) can be manufactured by reacting the compound
(xxxvii) obtained by the method from A to F or L with the compound
(xxxviii) in a solvent, such as THF and dioxane, in the presence of a
palladium catalyst and a solution, such as potassium carbonate, cesium
carbonate and sodium carbonate aqueous solution, etc., at a temperature
between 50° C. and reflux, preferably at reflux, or under
microwave irradiation at a temperature between 120 and 200° C.,
preferably at a temperature between 130 and 150° C.

(Step 2)

[0468] The compound (xl) can be obtained by dissolving the compound
(xxxix) in an alcohols solvent, such as methanol and ethanol, and
performing catalytic reduction using a hydrogenation reactor (such as
H-Cube (10% Pt--C, H2=1 atm)) or a metallic catalyst, such as
palladium-carbon, platinum oxide, chlorotris(triphenylphosphine)rhodium
(I), etc.

[Method N]

##STR00110##

[0469] wherein the symbols in the formula are as defined above.

(Step 1)

[0470] The compound (xlii) can be manufactured by reacting the compound
(xli) obtained by the method from A to F or L with the compound (xxxviii)
in a solvent, such as THF and dioxane, in the presence of a palladium
catalyst and a solution, such as potassium carbonate, cesium carbonate
and sodium carbonate aqueous solution, etc., at a temperature between
50° C. and reflux, preferably at reflux, or under microwave
irradiation at a temperature between 120 and 200° C., preferably
at a temperature between 130 and 150° C.

(Step 2)

[0471] The compound (xliii) can be obtained by dissolving the compound
(xlii) in an alcohols solvent, such as methanol and ethanol, and
performing catalytic reduction using a hydrogenation reactor (such as
H-Cube (10% Pt--C, H2=1 atm)) or a metallic catalyst, such as
palladium-carbon, platinum oxide and chlorotris (triphenylphosphine)
rhodium (I), etc.

[Method O]

##STR00111##

[0472] wherein R25 is substituted or unsubstituted alkyl or
substituted or unsubstituted alkoxy, R26 is bromo or iodo, and other
symbols are as defined above.

(Step 1)

[0473] The compound (xlvi) can be obtained from the compound (xlvi) in the
presence of Lewis acid or trifluoroacetic acid, etc., under solvent-free
conditions or in an appropriate solvent at a temperature between
0° C. and reflux.

(Step 2)

[0474] The compound (xlviii) can be manufactured by reacting the compound
(xlvi) with the compound (xlvii) in a solvent, such as THF and dioxane,
in the presence of a palladium catalyst and a solution, such as potassium
carbonate, cesium carbonate and sodium carbonate aqueous solution, etc.
at a temperature between 50° C. and reflux, preferably at reflux,
or under microwave irradiation at a temperature of 120 and 200°
C., preferably at a temperature between 130 and 150° C.

[Method P]

##STR00112##

[0475] wherein the symbols in the formula are as defined above.

(Step 1)

[0476] The compound (xli) can be manufactured by reacting a mixture of the
compound (iii) obtained by the method A, the alcohol (xl) and a solvent,
such as THF and dioxane, with triphenylphosphine, etc. and diethyl
azodicarboxylate, etc.

(Step 2)

[0477] The compound (xlii) can be manufactured by reacting the compound
(xli) with the compound (vi) in the presence of formic acid and acetic
acid, etc., at reflux.

[Method Q]

##STR00113##

[0478] wherein the symbols in the formula are as defined above.

(Step 1)

[0479] The compound (xliii) can be manufactured by reacting the compound
(v) obtained by the method A in a solvent, such as water, acetic acid and
methanol, in the presence of an oxidation agent, such as hydrogen
peroxide water and MCPBA, at a temperature between -20 and 100°
C., preferably at room temperature.

(Step 2)

[0480] The compound (xlv) can be manufactured by reacting the compound
(xliii) with the compound (xliv) in a solvent, such as acetonitrile,
acetone, DMF and DMSO, in the presence of a base, such as potassium
carbonate and sodium carbonate, at a temperature between 50° C.
and reflux, preferably at reflux.

[0481] The compounds of this invention (I) are not limited to a specific
isomer but include all possible isomers and racemates. For example, they
include a tautomer as shown below. The compounds indicated by the formula
(VIII), formula (IX) and formula (VII), etc., also include similar
tautomers.

##STR00114##

[0482] In addition, one or more hydrogen atoms, carbon atoms or other
atoms of the compound of the formula (I), formula (VIII), formula (IX),
formula (VII) and the like can be replaced by an isotope of the hydrogen
atom, carbon atom or other atoms. Compounds of the formula (I), formula
(VIII), formula (IX), formula (VII) and the like include all radiolabeled
forms of compounds of the formula (I), formula (VIII), formula (IX),
formula (VII) and the like. The "radiolabeled," "radiolabeled form" and
the like of the compound of the formula (I), formula (VIII), formula
(IX), formula (VII) and the like are encompassed by the present invention
and useful as a research and/or diagnostic tool in metabolism
pharmacokinetic studies and in binding assays. It is also useful for a
medicament.

[0483] Examples of isotopes that can be incorporated into the compound of
the formula (I), formula (VIII), formula (IX), formula (VIT) and the like
of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorous, sulfur, fluorine, iodine and chlorine, such as 2H,
3H, 11C, 13C, 14C, 15N, 18O, 17O,
31P, 32P, 35S, 18F, 123I and 36Cl,
respectively. Radiolabeled compounds of the present invention can be
prepared by methods known in the art. For example, tritiated compounds of
formula (I) can be prepared by introducing tritium into the particular
compound of formula (I), for example, by catalytic dehalogenation with
tritium. This method may include reacting a suitably halogen-substituted
precursor of a compound of formula (I), formula (VIII), formula (IX),
formula (VII) and the like with tritium gas in the presence of a suitable
catalyst such as Pd/C, in the presence or absence of a base. Other
suitable methods for preparing tritiated compounds can be found in
Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled
Compounds (Part A) Chapter 6, (1987). 14C-labeled compounds can be
prepared by employing starting materials having a 14C carbon.

[0484] The compounds of the above formula (I), formula (VIII), formula
(IX), formula (VII) and the like or its salt can be converted into
hydrate or solvate thereof by known methods. Examples of suitable
solvates are solvate with acetone, 2-butanol, 2-propanol, ethanol, ethyl
acetate, tetrahydrofuran, diethyl ether or the like. For example, it
includes a non-toxic and water-soluble hydrate or solvate such as a
solvate with ethanol.

[0486] The compound of the formula (I), formula (VIII), formula (IX),
formula (VII) and the like or its pharmaceutically acceptable salt may
form solvate such as hydrate, and/or crystalline polymorphism, and the
present invention also includes such various kinds of solvate and
crystalline polymorphism. The "solvate" includes a compound of the
formula (I), formula (VIII), formula (IX), formula (VII) and the like
which coordinate arbitrary number of solvent molecules such as water
molecules. The compound of the formula (I), formula (VIII), formula (IX),
formula (VII) and the like or its pharmaceutically acceptable salt can
adhere water or form hydrate by absorbing water molecules after leaving
in the atmosphere. Moreover, the compound of the formula (I), formula
(VIII), formula (IX), formula (VII) and the like or its pharmaceutically
acceptable salt can form the crystalline polymorphism by
recrystallization.

[0487] The compound of the formula (I), formula (VIII), formula (IX),
formula (VII) and the like of the present invention or its
pharmaceutically acceptable salt may form prodrug, and the present
invention also includes such various kinds of prodrug. Prodrug is a
derivative of the compound of the present invention having a group which
can be chemically or metabolically decomposed and the one which becomes a
pharmaceutically active compound of the present invention by solvolysis
or physiological conditions in vivo. Prodrug includes a compound which
converts into the compound of the formula (I), formula (VIII), formula
(IX), formula (VII) and the like by enzymatical oxidation, reduction,
hydrolysis or the like under physiological conditions in a living body,
and a compound which converts into the compound of the formula (I),
formula (VIII), formula (IX), formula (VII) and the like by hydrolyzing
by stomach acid or the like. The method of selecting suitable prodrug
derivatives and the method of manufacturing them are disclosed in Design
of Prodrugs, Elsevier, and Amsterdam 1985. Prodrug itself may possess the
activity.

[0488] When the compound of the formula (I), formula (VIII), formula (IX),
formula (VII) and the like or its pharmaceutically acceptable salt has a
hydroxy group, examples of the prodrug includes acyloxy derivatives and
sulfonyloxy derivatives which can be manufactured by reacting a compound
having a hydroxy group with a suitable acid halide, suitable acid
anhydride, suitable sulfonyl chloride, suitable sulfonylanhydride and
mixed anhydride. For example, CH3COO--, C2H5COO--,
t-BuCOO--, C15H31COO--, PhCOO--, (m-NaOOCPh)COO--,
NaOOCCH2CH2COO--, CH3CH(NH2)COO--,
CH2N(CH3)2COO--, CH3SO3--,
CH3CH2SO3--, CF3SO3--, CH3FSO3--,
CF3CH2SO3--, p-CH3--O-PhSO3--, PhSO3--, and
p-CH3PhSO3-- are exemplified.

[0491] The compound of the present invention or the pharmaceutical
composition of the present invention can be a drug with reduced
side-effect such as effect on motor function because it has a high
affinity for ATP receptor, especially P2X3 receptor, and also has
high subtype selectivity and high selectivity for other receptors. Also,
the compound encompassed by the present invention or the pharmaceutical
composition encompassed by the present invention is advantageous because
of its high P2X3 receptor inhibitor activity in the presence of RSA, high
metabolic stability, high oral absorption, good bioavailability, low
clearance, long half-life, prolonged duration of action, low activity of
hepatic enzyme inhibition, high unbound fraction in serum and/or high
safety etc.

[0492] In another embodiment, the present invention provides a
pharmaceutical composition comprising an effective amount of the compound
of the present invention, in combination with a pharmaceutically
acceptable carrier.

[0493] For use of the compound of the present invention as a medicament, a
pharmaceutical composition can be prepared according to conventional
methods, using pharmaceutically acceptable carriers well-known in the
art, such as excipients, binders, disintegrants, lubricants, colourants,
flavors, surfactants, etc.

[0494] For the pharmaceutical composition of the present invention to be
administered in the treatment of mammals including human, an appropriate
unit dosage form may be selected depending on the purpose of the
treatment and the route of administration. Specifically, such unit dosage
form includes oral formulations such as tablet, coated tablet, powder,
granule, capsule, liquid, pill, suspension, emulsion, etc., and
parenteral formulations such as injectable solution, suppository,
ointment, patch, aerosol, etc. Such unit dosage form can be formulated
according to methods well-known in the art.

[0495] The amount of the present compound in a formulation can vary
depending on its dosage form, route for administration, dosing regimen,
etc.

[0496] Means for administration of the present pharmaceutical composition
may be selected depending on dosage form, patient's age, sex, body
weight, severity of the disease, and other factors, etc., and route for
administration can be selected from various routes such as oral,
subcutaneous, transdermal, rectal, intranasal, buccal, etc.

[0497] Dose of the present compound in the present pharmaceutical
composition can be determined depending on the choice of route for
administration, patient's age, sex, body weight, severity of the disease,
the compound to be administered, and other factors, etc., and can be
generally from 0.05 to 1000 mg/kg/day, preferably from 0.1 to 10
mg/kg/day, for oral administration to adults. For parenteral
administration, dose can vary widely depending on its route but generally
from 0.005 to 100 mg/kg/day, preferably from 0.01 to 1 mg/kg/day. Such
pharmaceutical composition of the present invention may be administered
once a day or in several times at a divided dosage in a day.

[0498] In some embodiments of the present compounds, there is provided
compounds of the following general formula (V) and the general formula
(VI) having the following groups are provided:

Preparation of
1-(4-chlorobenzyl)-6-(methylthio)-1,3,5-triazine-2,4(1H,3H)-dion

##STR00119##

[0532] To a mixture of 1-(4-chlorobenzyl)thiourea (11.19 g, 55.8 mmol) and
methanol (50 mL) was added methyl iodide (4.18 ml, 66.9 mmol) under
ice-cooling, and the resulting mixture was stirred at room temperature
for 5 hours. The mixture was concentrated in vacuo. To the resulting
residue were added dichloromethane (60 ml) and N,N-diisopropylethylamine
(29.2 ml, 167 mmol), and then a solution of N-chlorocarbonyl isocyanate
(4.94 ml, 61.4 mmol) in dichloromethane (20 ml) was added gradually under
ice-cooling. The resulting mixture was stirred at room temperature for 1
hour. The precipitated solid was filtered off and the resulting solid was
washed by small amount on dichloromethane. The mixture was dried under
reduced pressure to give
1-(4-chlorobenzyl)-6-(methylthio)-1,3,5-triazine-2,4(1H,3H)-dion (9.19 g,
Yield: 58%) as colorless solid.

[0557] To a mixture of
1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(methoxycarbony-
lmethyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.30 g, 0.63 mmol), methanol (3
mL), and THF (3 mL) was added 1 mol/L lithium hydroxide (3.8 mL) under
ice-cooling, and the mixture was stirred at room temperature for 1 hour.
The pH of the mixture was adjusted with 2 mol/L hydrochloric acid to a pH
of less than 2. To the mixture was added brine (20 mL), and the resulting
mixture was extracted by chloroform (10 mL×3). The extract was
dried over anhydrous sodium sulphate and concentrated in vacuo. The
obtained residue was precipitated by diethyl ether and hexane to give
1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxy
phenylamino)-3-(hydroxycarbonylmethyl)-1,3,5-triazine-2,4(1H,3H)-dion
(0.28 g, Yield: 97%) as colorless solid.

[0566] To a mixture of 2-(tetrahydro-2H-pyrane-2-yloxy)ethanol (0.17 mL,
corresponding to 1.25 mmol) and THF (5.6 mL) was added 60% sodium hydride
(0.05 g, 1.25 mmol), and the mixture was stirred at room temperature for
10 minutes. To the mixture was added a solution of crude
4-chloro-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-tr-
iazine-2(1H)-one (0.224 g, corresponding to 0.5 mmol) in THF (2 mL) under
ice-cooling, and the resulting mixture was stirred at room temperature
for 5 hours. To the reaction mixture was added half-saturated aqueous
ammonium chloride (50 mL), and the mixture was extracted with ethyl
acetate (50 mL). The extract was washed by brine (10 mL), dried over
anhydrous sodium sulphate, and concentrated in vacuo. The resulting
residue was purified by silica gel column chromatography (ethyl
acetate/hexane). The obtained residue was precipitated by hexane to give
1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-4-(2-(tetrahydro--
2H-pyrane-2-yloxy)ethoxy)-1,3,5-triazine-2(1H)-one (0.166 g, Yield: 62%)
as colorless as oil.

[0573] To a mixture of 1-dodecanthiol (0.24 mL, 1.0 mmol) and THF (4.8 mL)
was added 60% sodium hydride (0.045 g, 1.0 mmol), and the mixture was
stirred at room temperature for minutes. To the resulting mixture was
added a solution of crude
4-chloro-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-tr-
iazine-2(1H)-one (0.19 g, corresponding to 0.4 mmol) in THF (2 mL) under
ice-cooling, and the mixture was stirred at 50° C. for 5 hours. To
the reaction mixture was added half-saturated aqueous ammonium chloride
(50 mL), and the mixture was extracted with ethyl acetate (50 mL). The
extract was washed by brine (10 mL), dried over anhydrous sodium
sulphate, and concentrated in vacuo. The resulting residue was purified
by silica gel column chromatography (ethyl acetate/hexane). The obtained
residue was precipitated by hexane to give
1-(4-chlorobenzyl)-4-(dodecylthio)-6-(3-fluoro-4-isopropoxyphenylamino)-1-
,3,5-triazine-2(1H)-one (0.092 g, Yield: 39%) as colorless oil.

[0576] To a mixture of
1-(4-chlorobenzyl)-6-(4-methoxycarbonylphenylamino)-3-isopropyl-1,3,5-tri-
azine-2,4(1H,3H)-dion (0.70 g, 1.63 mmol), methanol (4 mL) and TI-IF (4
mL) was added 2 mol/L lithium hydroxide (4.9 mL) under ice-cooling, and
the mixture was stirred at room temperature for 8 hours. The reaction
mixture was poured into water (50 mL), adjusted with 2 mol/L hydrochloric
acid to a pH of less than 3, and extracted with ethyl acetate (50
mL×2). The extract was washed by brine (50 mL), dried over
anhydrous sodium sulphate, and concentrated in vacuo. The resulting solid
was washed by diethyl ether to give 1-(4-chlorobenzyl)
6-(4-hydroxycarbonylphenylamino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-di-
on (0.60 g, Yield: 89%) as colorless solid.

[0593] To a mixture of
(R)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2-methoxyc-
arbonylpropyl)-1,3,5-triazinane-2,4-dion (0.26 g, 0.5 mmol) and dioxane (4
mL) was added 1 mol/L lithium hydroxide (1.6 mL), and the mixture was
stirred at 50° C. for 6 hours. To the mixture was added water (50
mL), adjusted with 2 mol/L hydrochloric acid to a pH of about 3, and the
precipitated solid was filtered off. The solid was dried at 40° C.
to give (R)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2--
hydroxycarbonylpropyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.21 g, Yield: 84%)
as colorless solid.

Preparation of
1-(4-chlorobenzyl)-6-(Ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion

##STR00139##

[0605] To a mixture of S-ethylisothiourea hydrobromide (1.85 g, 10 mmol)
and DMF (9.3 mL) were added t-butylisocyanide (1.2 mL, 10.5 mmol) and DBU
(1.9 mL, 12.8 mmol) under ice-cooling, and the mixture was stirred under
ice-cooling for 6 hours. To the reaction mixture were added
1,1'-carbonyldiimidazole (1.95 g, 12 mmol) and DBU (1.9 mL, 12.8 mmol)
under ice-cooling, and the resulting mixture was stirred for additional 2
hours. To the mixture was added 2 mol/L hydrochloric acid (80 mL) under
ice-cooling over about 50 minutes, and the precipitated solid was
filtered off. The resulting solid was dissolved in ethyl acetate, and the
mixture was dried over anhydrous magnesium sulfate and concentrated in
vacuo to give 6-(ethylthio)-3-t-butyl-1,3,5-triazine-2,4(1H,3H)-dion
(1.15 g. Yield: 50%) as pale brown solid.

[0607] To a mixture of
6-(ethylthio)-3-t-butyl-1,3,5-triazine-2,4(1H,3H)-dion (22.93 g, 100
mmol), 4-chlorobenzylbromide (22.60 g, 110 mmol) and acetonitrile (200
mL) was added potassium carbonate (17.97 g, 130 mmol), and the mixture
was heated at reflux for 3 hours. The reaction mixture was filtered to
remove the insoluble. The filtrate was concentrated in vacuo to give 39.9
g of crude
3-t-butyl-1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion
as pale brown oil. To the obtained crude product was added
trifluoroacetic acid (100 mL) under ice-cooling, and the mixture was
stirred at room temperature for 17 hours. The reaction mixture was
concentrated in vacuo to give crude residue. The residue was precipitated
to give 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion
(29.03 g, Yield: 97%) as pale brown solid.

[0621] To a mixture of sodium methoxide (34.1 mg, 0.63 mmol and methanol
(2 mL) was added hydroxylamine hydrochloride (43.8 mg, 0.631 mmol) under
ice-cooling. After the mixture was neutralized,
1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-cyanomethyl-1,3-
,5-triazinane-2,4-dion (0.14 g, 0.315 mmol) was added and the resulting
mixture was heated at reflux for 2 hours. To the mixture was added water
(150 mL), and the mixture was extracted with ethyl acetate (150 mL). The
extract was washed by brine (150 mL), dried over anhydrous magnesium
sulfate, and concentrated in vacuo. The resulting residue was
precipitated by ethyl ether to give
1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxy
phenylimino)-3-(2-amino-2-hydroxyiminoethyl)-1,3,5-triazinane-2,4-dion
(91 mg, Yield: 61%) as colorless solid.

[0629] To a solution of
(R)-1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-[(2,2-dimet-
hyl-1,3-dioxolane-4-yl)methyl]-1,3,5-triazinane-2,4-dion (110 mg, 0.205
mmol) in methanol (4 mL) was added p-toluenesulfonic acid monohydrate (59
mg, 0.31 mmol), and the mixture was stirred at room temperature for 5
hours. The reaction mixture was concentrated, and the residue was
extracted with ethyl acetate. The extract was washed by water, dried over
anhydrous sodium sulphate, and concentrated in vacuo. The resulting
residue was precipitated by dichloromethane and hexane to give
(R)-1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-(2,3-dihydr-
oxypropyl)-1,3,5-triazinane-2,4-dion (88 mg, Yield: 86%) as colorless
solid.

[0632] To a mixture of S-ethylisothiourea hydrobromide (6.00 g, 32.4 mmol)
and DMF (30 mL) were added ethyl 6-isocyanatocaproate (4.48 mL, 34.0
mmol) and DBU (5.1.3 mL, 34.0 mmol) under ice-cooling, and the mixture
was stirred under ice-cooling for 5 hours. To the reaction mixture were
added 1,1'-carbonyldiimidazole (6.31 g, 38.9 mmol) and DBU (7.33 mL, 49.0
mmol) under ice-cooling, and the mixture was stirred at room temperature
for 1 hour. To the reaction mixture was added 2 mol/L hydrochloric acid
(96 mL) under ice-cooling over 15 minutes, and the mixture was extracted
with ethyl acetate. The extract was washed by water and brine, dried over
anhydrous sodium sulphate. The extract was concentrated in vacuo to give
6-(ethylthio)-3-(2-ethoxycarbonylethyl)-1,3,5-triazine-2,4(1H,3H)-dion
(7.86 g, Yield: 89%) as colorless solid.

[0642] To a mixture of
1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-1,3,5-triazine-2,-
4(1H,3H)-dion (2 g, 4.94 mmol) and DMF (30 mL) was added potassium
tert-butoxide (1.331 g, 11.86 mmol) at room temperature and the resulting
mixture was stirred for 5 minutes. Further, to the reaction mixture was
added methylacrylate (1.074 mL, 11.86 mmol), and the resulting mixture
was stirred at 60° C. for 1.5 hours. To the reaction mixture were
added potassium tert-butoxide (0.554 g, 4.94 mmol) and methylacrylate
(0.448 mL, 4.94 mmol), and the resulting mixture was stirred at
60° C. for 2 hours. Water (0.5 mL) was added to the mixture and
the resulting mixture was stirred at 80° C. for 2 hours. The
reaction mixture was concentrated in vacuo and 2 mol/L aqueous
hydrochloric acid (80 mL) was added to the resulting residue. The mixture
was extracted with ethyl acetate (50 mL×3). The extract was washed
by brine (100 mL), dried over anhydrous sodium sulphate, and concentrated
in vacuo. The resulting residue was purified by silica gel column
chromatography (methanol/chloroform). The resulting residue was
precipitated by ethyl acetate and hexane to give
1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-hydroxycarbo-
nylethyl) 1,3,5-triazinane-2,4-dion (1.64 g, Yield: 70%) as colorless
solid.

[0647] To a mixture of
1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-hydrazinecar-
bonylethyl-1,3,5-triazinane-2,4-dion (134.6 mg, 0.274 mmol) and DMF (2 mL)
was added 1,1'-carbonyldiimidazole (53.3 mg, 0.329 mmol), and the mixture
was stirred at room temperature overnight. The mixture was added to water
(200 mL), and extracted with ethyl acetate (300 mL). The extract was
washed by brine (200 mL), dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The resulting residue was precipitated by hexane
to give 1-(4-chlorobenzyl-6-(3-fluoro-4-isopropoxyphenylimino)-3-(5-oxo-4-
,5-dihydro-1,3,4-oxadiazol-2-yl)methyl-1,3,5-triazinane-2,4-dion (113 mg,
Yield: 80%) as colorless powder.

[0652] A mixture of
1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-carbamoyleth-
yl)-1,3,5-triazinane-2,4-dion (150 mg, 0.315 mmol) and
N,N-dimethylformamide dimethyl acetal (2 mL) was stirred at 80° C.
for 1.5 hours. The reaction mixture was concentrated in vacuo. To the
residue were added acetic acid (1 mL) and hydrazine monohydrate (0.046
mL, 0.944 mmol), and the mixture was stirred at 90° C. for 0.5
hour. The reaction mixture was poured into water (200 mL), and the
resulting mixture was extracted with chloroform (200 mL×2). The
extract was dried over anhydrous sodium sulphate, and concentrated in
vacuo. The resulting residue was precipitated by ethyl acetate and hexane
to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-[2-(1,2-
,4-triazol-5-yl)ethyl]-1,3,5-triazinane-2,4-dion (75.3 mg, Yield: 48%) as
colorless powder.

[0691] To 1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-sulfoethyl)-1,3,5-triazine-
-2,4(1H,3H)-dion (120 mg, 0.296 mmol) was added phosphorus oxychloride
(2.5 mL), and the mixture was heated at reflux for 2 hours. The reaction
mixture was concentrated in vacuo and the resulting residue was dissolved
in dioxane (5 mL). The dioxane solution of the residue was gradually
added to 0.5 mol/L ammonia in dioxane (5.9 mL) under ice-cooling, and the
resulting mixture was stirred at room temperature overnight. The
precipitated insoluble were filtered off and the filtrate was
concentrated in vacuo. The resulting residue was purified by HPLC to give
1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-sulfamoylethyl)-1,3,5-triazine-2,4(-
1H,3H)-dion (7.4 mg, Yield: 6%) as colorless solid.

[0710] To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxy
phenylimino)-3-(2-ethoxycarbonyl-2-methoxyiminoethyl)-1,3,5-triazinane-2,-
4-dion (0.29 g, 0.53 mmol), methanol (3 mL) and water (1.5 mL) was added 4
mol/L lithium hydroxide (0.4 mL), and the resulting mixture was stirred
at room temperature overnight. To the reaction mixture was added water
(100 mL). The pH of the mixture was adjusted with 2 mol/L hydrochloric
acid to a pH of about 3, and the resulting mixture was extracted with
ethyl acetate (200 mL). The extract was washed by brine (200 mL), dried
over anhydrous magnesium sulfate, and concentrated in vacuo. The
resulting residue was precipitated by ethyl acetate and hexane to give
1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxy
phenylimino)-3-(2-hydroxycarbonyl-2-methoxyiminoethyl)-1,3,5-triazinane-2-
,4-dion (0.27 g, Yield: 99%) as colorless powder.

[0793] A solution of
(S)-1-(4-chlorobenzyl)-6-(2,4-dimethoxy-benzylimino)-3-(2-methoxycarbonyl-
propyl)methyl-1,3,5-triazinane-2,4-dion (1.15 g, 2.29 mmol) in trifluoro
acetic acid (1 mL) was stirred at room temperature for 1 hour. The
reaction mixture was concentrated in vacuo, and the residue was extracted
with chloroform. The extract was washed by saturated aqueous sodium
bicarbonate and brine, dried over anhydrous sodium sulphate, and
concentrated in vacuo. The resulting residue was precipitated by ethyl
acetate and hexane to give
(S)-6-amino-1-(4-chlorobenzyl)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-tr-
iazine-2,4(1H,3H)-dion (0.80 g, Yield: 99%) as colorless solid.

[0812] To a mixture of 1-(4-chlorobenzyl)-6-(methylthio)-3
isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (0.2 g, 0.6 mmol) and acetic
acid (10 mL) was added 30% hydrogen peroxide solution (0.7 g, 6 mmol)
under ice-cooling, and the resulting mixture was stirred at room
temperature for 18 hours. To the reaction mixture was added brine (30
mL), and the resulting mixture was extracted with dichloromethane (30
mL×2). The extract was washed by brine (30 mL), dried over
anhydrous sodium sulphate, and concentrated in vacuo. The resulting
residue was precipitated by hexane to give
1-(4-chlorobenzyl)-3-isopropyl-1,3,5-triazine-2,4,6-trione (0.2 g) as a
white powder.

[0822] The thiourea derivative (200 mg, 0.477 mmol) was dissolved in THF
(2.0 mL), and carbonyldiimidazole (77 mg, 0.477 mmol) was added to the
solution under ice-cooling. The resulting mixture was heated at reflux
for 22 hours under nitrogen atmosphere. Further, carbonyldiimidazole (77
mg, 0.477 mmol) and triethylamine (0.066 mL, 0.477 mmol) were added to
the mixture, and the resulting mixture was heated at reflux for 3.5
hours. To the mixture was added ethyl acetate (50 mL), and the resulting
mixture was washed by water (20 mL×2) and brine (10 mL). The
organic layer was dried over anhydrous sodium sulphate and concentrated
in vacuo. The resulting residue was purified by silica gel column
chromatography (ethyl acetate/hexane), and the resulting residue was
precipitated by ethyl acetate/hexane to give aimed
1-(4-chlorobenzyl)-3-isopropyl-6-(4-isopropoxyphenylimino)-4-thioxo-1,3,5-
-triazinane-2-one (8.3 mg, Yield: 3.9%) as a white powder.

[0856] The following compound of the invention and intermediate thereof
were synthesized in a manner similar to those described in the above
general procedures for the synthesis of the compound of the invention and
Examples. The chemical structure of the compounds and the physical
properties of them are described below.

(Method of Identification for the Compound)

[0857] LC/MS data of compound of the present invention were measured under
any one of the following 2 conditions (Method 1 and 2), and a retention
time and [M+H]+ are shown.

TABLE-US-00004
Lengthy table referenced here
US20130172317A1-20130704-T00001
Please refer to the end of the specification for access instructions.

TABLE-US-00005
Lengthy table referenced here
US20130172317A1-20130704-T00002
Please refer to the end of the specification for access instructions.

TABLE-US-00006
Lengthy table referenced here
US20130172317A1-20130704-T00003
Please refer to the end of the specification for access instructions.

TABLE-US-00007
Lengthy table referenced here
US20130172317A1-20130704-T00004
Please refer to the end of the specification for access instructions.

TABLE-US-00008
Lengthy table referenced here
US20130172317A1-20130704-T00005
Please refer to the end of the specification for access instructions.

TABLE-US-00009
Lengthy table referenced here
US20130172317A1-20130704-T00006
Please refer to the end of the specification for access instructions.

TABLE-US-00010
Lengthy table referenced here
US20130172317A1-20130704-T00007
Please refer to the end of the specification for access instructions.

TABLE-US-00011
Lengthy table referenced here
US20130172317A1-20130704-T00008
Please refer to the end of the specification for access instructions.

TABLE-US-00012
Lengthy table referenced here
US20130172317A1-20130704-T00009
Please refer to the end of the specification for access instructions.

TABLE-US-00013
Lengthy table referenced here
US20130172317A1-20130704-T00010
Please refer to the end of the specification for access instructions.

TABLE-US-00014
Lengthy table referenced here
US20130172317A1-20130704-T00011
Please refer to the end of the specification for access instructions.

TABLE-US-00015
Lengthy table referenced here
US20130172317A1-20130704-T00012
Please refer to the end of the specification for access instructions.

TABLE-US-00016
Lengthy table referenced here
US20130172317A1-20130704-T00013
Please refer to the end of the specification for access instructions.

TABLE-US-00017
Lengthy table referenced here
US20130172317A1-20130704-T00014
Please refer to the end of the specification for access instructions.

TABLE-US-00018
Lengthy table referenced here
US20130172317A1-20130704-T00015
Please refer to the end of the specification for access instructions.

TABLE-US-00019
Lengthy table referenced here
US20130172317A1-20130704-T00016
Please refer to the end of the specification for access instructions.

TABLE-US-00020
Lengthy table referenced here
US20130172317A1-20130704-T00017
Please refer to the end of the specification for access instructions.

TABLE-US-00021
Lengthy table referenced here
US20130172317A1-20130704-T00018
Please refer to the end of the specification for access instructions.

TABLE-US-00022
Lengthy table referenced here
US20130172317A1-20130704-T00019
Please refer to the end of the specification for access instructions.

TABLE-US-00023
Lengthy table referenced here
US20130172317A1-20130704-T00020
Please refer to the end of the specification for access instructions.

TABLE-US-00024
Lengthy table referenced here
US20130172317A1-20130704-T00021
Please refer to the end of the specification for access instructions.

TABLE-US-00025
Lengthy table referenced here
US20130172317A1-20130704-T00022
Please refer to the end of the specification for access instructions.

TABLE-US-00026
Lengthy table referenced here
US20130172317A1-20130704-T00023
Please refer to the end of the specification for access instructions.

TABLE-US-00027
Lengthy table referenced here
US20130172317A1-20130704-T00024
Please refer to the end of the specification for access instructions.

TABLE-US-00028
Lengthy table referenced here
US20130172317A1-20130704-T00025
Please refer to the end of the specification for access instructions.

TABLE-US-00029
Lengthy table referenced here
US20130172317A1-20130704-T00026
Please refer to the end of the specification for access instructions.

TABLE-US-00030
Lengthy table referenced here
US20130172317A1-20130704-T00027
Please refer to the end of the specification for access instructions.

TABLE-US-00031
Lengthy table referenced here
US20130172317A1-20130704-T00028
Please refer to the end of the specification for access instructions.

TABLE-US-00032
Lengthy table referenced here
US20130172317A1-20130704-T00029
Please refer to the end of the specification for access instructions.

TABLE-US-00033
Lengthy table referenced here
US20130172317A1-20130704-T00030
Please refer to the end of the specification for access instructions.

TABLE-US-00034
Lengthy table referenced here
US20130172317A1-20130704-T00031
Please refer to the end of the specification for access instructions.

TABLE-US-00035
Lengthy table referenced here
US20130172317A1-20130704-T00032
Please refer to the end of the specification for access instructions.

TABLE-US-00036
Lengthy table referenced here
US20130172317A1-20130704-T00033
Please refer to the end of the specification for access instructions.

TABLE-US-00037
Lengthy table referenced here
US20130172317A1-20130704-T00034
Please refer to the end of the specification for access instructions.

TABLE-US-00038
Lengthy table referenced here
US20130172317A1-20130704-T00035
Please refer to the end of the specification for access instructions.

TABLE-US-00039
Lengthy table referenced here
US20130172317A1-20130704-T00036
Please refer to the end of the specification for access instructions.

TABLE-US-00040
Lengthy table referenced here
US20130172317A1-20130704-T00037
Please refer to the end of the specification for access instructions.

TABLE-US-00041
Lengthy table referenced here
US20130172317A1-20130704-T00038
Please refer to the end of the specification for access instructions.

TABLE-US-00042
Lengthy table referenced here
US20130172317A1-20130704-T00039
Please refer to the end of the specification for access instructions.

TABLE-US-00043
Lengthy table referenced here
US20130172317A1-20130704-T00040
Please refer to the end of the specification for access instructions.

TABLE-US-00044
Lengthy table referenced here
US20130172317A1-20130704-T00041
Please refer to the end of the specification for access instructions.

TABLE-US-00045
Lengthy table referenced here
US20130172317A1-20130704-T00042
Please refer to the end of the specification for access instructions.

TABLE-US-00046
Lengthy table referenced here
US20130172317A1-20130704-T00043
Please refer to the end of the specification for access instructions.

TABLE-US-00047
Lengthy table referenced here
US20130172317A1-20130704-T00044
Please refer to the end of the specification for access instructions.

TABLE-US-00048
Lengthy table referenced here
US20130172317A1-20130704-T00045
Please refer to the end of the specification for access instructions.

TABLE-US-00049
Lengthy table referenced here
US20130172317A1-20130704-T00046
Please refer to the end of the specification for access instructions.

TABLE-US-00050
Lengthy table referenced here
US20130172317A1-20130704-T00047
Please refer to the end of the specification for access instructions.

TABLE-US-00051
Lengthy table referenced here
US20130172317A1-20130704-T00048
Please refer to the end of the specification for access instructions.

TABLE-US-00052
Lengthy table referenced here
US20130172317A1-20130704-T00049
Please refer to the end of the specification for access instructions.

TABLE-US-00053
Lengthy table referenced here
US20130172317A1-20130704-T00050
Please refer to the end of the specification for access instructions.

TABLE-US-00054
Lengthy table referenced here
US20130172317A1-20130704-T00051
Please refer to the end of the specification for access instructions.

TABLE-US-00055
Lengthy table referenced here
US20130172317A1-20130704-T00052
Please refer to the end of the specification for access instructions.

TABLE-US-00056
Lengthy table referenced here
US20130172317A1-20130704-T00053
Please refer to the end of the specification for access instructions.

TABLE-US-00057
Lengthy table referenced here
US20130172317A1-20130704-T00054
Please refer to the end of the specification for access instructions.

TABLE-US-00058
Lengthy table referenced here
US20130172317A1-20130704-T00055
Please refer to the end of the specification for access instructions.

TABLE-US-00059
Lengthy table referenced here
US20130172317A1-20130704-T00056
Please refer to the end of the specification for access instructions.

TABLE-US-00060
Lengthy table referenced here
US20130172317A1-20130704-T00057
Please refer to the end of the specification for access instructions.

TABLE-US-00061
Lengthy table referenced here
US20130172317A1-20130704-T00058
Please refer to the end of the specification for access instructions.

TABLE-US-00062
Lengthy table referenced here
US20130172317A1-20130704-T00059
Please refer to the end of the specification for access instructions.

TABLE-US-00063
Lengthy table referenced here
US20130172317A1-20130704-T00060
Please refer to the end of the specification for access instructions.

TABLE-US-00064
Lengthy table referenced here
US20130172317A1-20130704-T00061
Please refer to the end of the specification for access instructions.

TABLE-US-00065
Lengthy table referenced here
US20130172317A1-20130704-T00062
Please refer to the end of the specification for access instructions.

TABLE-US-00066
Lengthy table referenced here
US20130172317A1-20130704-T00063
Please refer to the end of the specification for access instructions.

TABLE-US-00067
Lengthy table referenced here
US20130172317A1-20130704-T00064
Please refer to the end of the specification for access instructions.

TABLE-US-00068
Lengthy table referenced here
US20130172317A1-20130704-T00065
Please refer to the end of the specification for access instructions.

TABLE-US-00069
Lengthy table referenced here
US20130172317A1-20130704-T00066
Please refer to the end of the specification for access instructions.

TABLE-US-00070
Lengthy table referenced here
US20130172317A1-20130704-T00067
Please refer to the end of the specification for access instructions.

TABLE-US-00071
Lengthy table referenced here
US20130172317A1-20130704-T00068
Please refer to the end of the specification for access instructions.

TABLE-US-00072
Lengthy table referenced here
US20130172317A1-20130704-T00069
Please refer to the end of the specification for access instructions.

TABLE-US-00073
Lengthy table referenced here
US20130172317A1-20130704-T00070
Please refer to the end of the specification for access instructions.

TABLE-US-00074
Lengthy table referenced here
US20130172317A1-20130704-T00071
Please refer to the end of the specification for access instructions.

TABLE-US-00075
Lengthy table referenced here
US20130172317A1-20130704-T00072
Please refer to the end of the specification for access instructions.

TABLE-US-00076
Lengthy table referenced here
US20130172317A1-20130704-T00073
Please refer to the end of the specification for access instructions.

TABLE-US-00077
Lengthy table referenced here
US20130172317A1-20130704-T00074
Please refer to the end of the specification for access instructions.

TABLE-US-00078
Lengthy table referenced here
US20130172317A1-20130704-T00075
Please refer to the end of the specification for access instructions.

TABLE-US-00079
Lengthy table referenced here
US20130172317A1-20130704-T00076
Please refer to the end of the specification for access instructions.

TABLE-US-00080
Lengthy table referenced here
US20130172317A1-20130704-T00077
Please refer to the end of the specification for access instructions.

TABLE-US-00081
Lengthy table referenced here
US20130172317A1-20130704-T00078
Please refer to the end of the specification for access instructions.

TABLE-US-00082
Lengthy table referenced here
US20130172317A1-20130704-T00079
Please refer to the end of the specification for access instructions.

TABLE-US-00083
Lengthy table referenced here
US20130172317A1-20130704-T00080
Please refer to the end of the specification for access instructions.

TABLE-US-00084
Lengthy table referenced here
US20130172317A1-20130704-T00081
Please refer to the end of the specification for access instructions.

TABLE-US-00085
Lengthy table referenced here
US20130172317A1-20130704-T00082
Please refer to the end of the specification for access instructions.

TABLE-US-00086
Lengthy table referenced here
US20130172317A1-20130704-T00083
Please refer to the end of the specification for access instructions.

TABLE-US-00087
Lengthy table referenced here
US20130172317A1-20130704-T00084
Please refer to the end of the specification for access instructions.

TABLE-US-00088
Lengthy table referenced here
US20130172317A1-20130704-T00085
Please refer to the end of the specification for access instructions.

TABLE-US-00089
Lengthy table referenced here
US20130172317A1-20130704-T00086
Please refer to the end of the specification for access instructions.

TABLE-US-00090
Lengthy table referenced here
US20130172317A1-20130704-T00087
Please refer to the end of the specification for access instructions.

TABLE-US-00091
Lengthy table referenced here
US20130172317A1-20130704-T00088
Please refer to the end of the specification for access instructions.

TABLE-US-00092
Lengthy table referenced here
US20130172317A1-20130704-T00089
Please refer to the end of the specification for access instructions.

TABLE-US-00093
Lengthy table referenced here
US20130172317A1-20130704-T00090
Please refer to the end of the specification for access instructions.

TABLE-US-00094
Lengthy table referenced here
US20130172317A1-20130704-T00091
Please refer to the end of the specification for access instructions.

TABLE-US-00095
Lengthy table referenced here
US20130172317A1-20130704-T00092
Please refer to the end of the specification for access instructions.

TABLE-US-00096
Lengthy table referenced here
US20130172317A1-20130704-T00093
Please refer to the end of the specification for access instructions.

TABLE-US-00097
Lengthy table referenced here
US20130172317A1-20130704-T00094
Please refer to the end of the specification for access instructions.

TABLE-US-00098
Lengthy table referenced here
US20130172317A1-20130704-T00095
Please refer to the end of the specification for access instructions.

TABLE-US-00099
Lengthy table referenced here
US20130172317A1-20130704-T00096
Please refer to the end of the specification for access instructions.

TABLE-US-00100
Lengthy table referenced here
US20130172317A1-20130704-T00097
Please refer to the end of the specification for access instructions.

TABLE-US-00101
Lengthy table referenced here
US20130172317A1-20130704-T00098
Please refer to the end of the specification for access instructions.

TABLE-US-00102
Lengthy table referenced here
US20130172317A1-20130704-T00099
Please refer to the end of the specification for access instructions.

TABLE-US-00103
Lengthy table referenced here
US20130172317A1-20130704-T00100
Please refer to the end of the specification for access instructions.

TABLE-US-00104
Lengthy table referenced here
US20130172317A1-20130704-T00101
Please refer to the end of the specification for access instructions.

TABLE-US-00105
Lengthy table referenced here
US20130172317A1-20130704-T00102
Please refer to the end of the specification for access instructions.

TABLE-US-00106
Lengthy table referenced here
US20130172317A1-20130704-T00103
Please refer to the end of the specification for access instructions.

TABLE-US-00107
Lengthy table referenced here
US20130172317A1-20130704-T00104
Please refer to the end of the specification for access instructions.

TABLE-US-00108
Lengthy table referenced here
US20130172317A1-20130704-T00105
Please refer to the end of the specification for access instructions.

TABLE-US-00109
Lengthy table referenced here
US20130172317A1-20130704-T00106
Please refer to the end of the specification for access instructions.

TABLE-US-00110
Lengthy table referenced here
US20130172317A1-20130704-T00107
Please refer to the end of the specification for access instructions.

TABLE-US-00111
Lengthy table referenced here
US20130172317A1-20130704-T00108
Please refer to the end of the specification for access instructions.

TABLE-US-00112
Lengthy table referenced here
US20130172317A1-20130704-T00109
Please refer to the end of the specification for access instructions.

TABLE-US-00113
Lengthy table referenced here
US20130172317A1-20130704-T00110
Please refer to the end of the specification for access instructions.

TABLE-US-00114
Lengthy table referenced here
US20130172317A1-20130704-T00111
Please refer to the end of the specification for access instructions.

TABLE-US-00115
Lengthy table referenced here
US20130172317A1-20130704-T00112
Please refer to the end of the specification for access instructions.

TABLE-US-00116
Lengthy table referenced here
US20130172317A1-20130704-T00113
Please refer to the end of the specification for access instructions.

TABLE-US-00117
Lengthy table referenced here
US20130172317A1-20130704-T00114
Please refer to the end of the specification for access instructions.

TABLE-US-00118
Lengthy table referenced here
US20130172317A1-20130704-T00115
Please refer to the end of the specification for access instructions.

TABLE-US-00119
Lengthy table referenced here
US20130172317A1-20130704-T00116
Please refer to the end of the specification for access instructions.

TABLE-US-00120
Lengthy table referenced here
US20130172317A1-20130704-T00117
Please refer to the end of the specification for access instructions.

TABLE-US-00121
Lengthy table referenced here
US20130172317A1-20130704-T00118
Please refer to the end of the specification for access instructions.

TABLE-US-00122
Lengthy table referenced here
US20130172317A1-20130704-T00119
Please refer to the end of the specification for access instructions.

TABLE-US-00123
Lengthy table referenced here
US20130172317A1-20130704-T00120
Please refer to the end of the specification for access instructions.

TABLE-US-00124
Lengthy table referenced here
US20130172317A1-20130704-T00121
Please refer to the end of the specification for access instructions.

TABLE-US-00125
Lengthy table referenced here
US20130172317A1-20130704-T00122
Please refer to the end of the specification for access instructions.

TABLE-US-00126
Lengthy table referenced here
US20130172317A1-20130704-T00123
Please refer to the end of the specification for access instructions.

TABLE-US-00127
Lengthy table referenced here
US20130172317A1-20130704-T00124
Please refer to the end of the specification for access instructions.

TABLE-US-00128
Lengthy table referenced here
US20130172317A1-20130704-T00125
Please refer to the end of the specification for access instructions.

TABLE-US-00129
Lengthy table referenced here
US20130172317A1-20130704-T00126
Please refer to the end of the specification for access instructions.

TABLE-US-00130
Lengthy table referenced here
US20130172317A1-20130704-T00127
Please refer to the end of the specification for access instructions.

TABLE-US-00131
Lengthy table referenced here
US20130172317A1-20130704-T00128
Please refer to the end of the specification for access instructions.

TABLE-US-00132
Lengthy table referenced here
US20130172317A1-20130704-T00129
Please refer to the end of the specification for access instructions.

TABLE-US-00133
Lengthy table referenced here
US20130172317A1-20130704-T00130
Please refer to the end of the specification for access instructions.

TABLE-US-00134
Lengthy table referenced here
US20130172317A1-20130704-T00131
Please refer to the end of the specification for access instructions.

TABLE-US-00135
Lengthy table referenced here
US20130172317A1-20130704-T00132
Please refer to the end of the specification for access instructions.

TABLE-US-00136
Lengthy table referenced here
US20130172317A1-20130704-T00133
Please refer to the end of the specification for access instructions.

TABLE-US-00137
Lengthy table referenced here
US20130172317A1-20130704-T00134
Please refer to the end of the specification for access instructions.

TABLE-US-00138
Lengthy table referenced here
US20130172317A1-20130704-T00135
Please refer to the end of the specification for access instructions.

TABLE-US-00139
Lengthy table referenced here
US20130172317A1-20130704-T00136
Please refer to the end of the specification for access instructions.

TABLE-US-00140
Lengthy table referenced here
US20130172317A1-20130704-T00137
Please refer to the end of the specification for access instructions.

TABLE-US-00141
Lengthy table referenced here
US20130172317A1-20130704-T00138
Please refer to the end of the specification for access instructions.

TABLE-US-00142
Lengthy table referenced here
US20130172317A1-20130704-T00139
Please refer to the end of the specification for access instructions.

TABLE-US-00143
Lengthy table referenced here
US20130172317A1-20130704-T00140
Please refer to the end of the specification for access instructions.

TABLE-US-00144
Lengthy table referenced here
US20130172317A1-20130704-T00141
Please refer to the end of the specification for access instructions.

TABLE-US-00145
Lengthy table referenced here
US20130172317A1-20130704-T00142
Please refer to the end of the specification for access instructions.

TABLE-US-00146
Lengthy table referenced here
US20130172317A1-20130704-T00143
Please refer to the end of the specification for access instructions.

TABLE-US-00147
Lengthy table referenced here
US20130172317A1-20130704-T00144
Please refer to the end of the specification for access instructions.

TABLE-US-00148
Lengthy table referenced here
US20130172317A1-20130704-T00145
Please refer to the end of the specification for access instructions.

TABLE-US-00149
Lengthy table referenced here
US20130172317A1-20130704-T00146
Please refer to the end of the specification for access instructions.

TABLE-US-00150
Lengthy table referenced here
US20130172317A1-20130704-T00147
Please refer to the end of the specification for access instructions.

TABLE-US-00151
Lengthy table referenced here
US20130172317A1-20130704-T00148
Please refer to the end of the specification for access instructions.

TABLE-US-00152
Lengthy table referenced here
US20130172317A1-20130704-T00149
Please refer to the end of the specification for access instructions.

TABLE-US-00153
Lengthy table referenced here
US20130172317A1-20130704-T00150
Please refer to the end of the specification for access instructions.

TABLE-US-00154
Lengthy table referenced here
US20130172317A1-20130704-T00151
Please refer to the end of the specification for access instructions.

TABLE-US-00155
Lengthy table referenced here
US20130172317A1-20130704-T00152
Please refer to the end of the specification for access instructions.

TABLE-US-00156
Lengthy table referenced here
US20130172317A1-20130704-T00153
Please refer to the end of the specification for access instructions.

TABLE-US-00157
Lengthy table referenced here
US20130172317A1-20130704-T00154
Please refer to the end of the specification for access instructions.

TABLE-US-00158
Lengthy table referenced here
US20130172317A1-20130704-T00155
Please refer to the end of the specification for access instructions.

TABLE-US-00159
Lengthy table referenced here
US20130172317A1-20130704-T00156
Please refer to the end of the specification for access instructions.

TABLE-US-00160
Lengthy table referenced here
US20130172317A1-20130704-T00157
Please refer to the end of the specification for access instructions.

TABLE-US-00161
Lengthy table referenced here
US20130172317A1-20130704-T00158
Please refer to the end of the specification for access instructions.

TABLE-US-00162
Lengthy table referenced here
US20130172317A1-20130704-T00159
Please refer to the end of the specification for access instructions.

TABLE-US-00163
Lengthy table referenced here
US20130172317A1-20130704-T00160
Please refer to the end of the specification for access instructions.

TABLE-US-00164
Lengthy table referenced here
US20130172317A1-20130704-T00161
Please refer to the end of the specification for access instructions.

TABLE-US-00165
Lengthy table referenced here
US20130172317A1-20130704-T00162
Please refer to the end of the specification for access instructions.

TABLE-US-00166
Lengthy table referenced here
US20130172317A1-20130704-T00163
Please refer to the end of the specification for access instructions.

TABLE-US-00167
Lengthy table referenced here
US20130172317A1-20130704-T00164
Please refer to the end of the specification for access instructions.

TABLE-US-00168
Lengthy table referenced here
US20130172317A1-20130704-T00165
Please refer to the end of the specification for access instructions.

TABLE-US-00169
Lengthy table referenced here
US20130172317A1-20130704-T00166
Please refer to the end of the specification for access instructions.

TABLE-US-00170
Lengthy table referenced here
US20130172317A1-20130704-T00167
Please refer to the end of the specification for access instructions.

TABLE-US-00171
Lengthy table referenced here
US20130172317A1-20130704-T00168
Please refer to the end of the specification for access instructions.

TABLE-US-00172
Lengthy table referenced here
US20130172317A1-20130704-T00169
Please refer to the end of the specification for access instructions.

TABLE-US-00173
Lengthy table referenced here
US20130172317A1-20130704-T00170
Please refer to the end of the specification for access instructions.

TABLE-US-00174
Lengthy table referenced here
US20130172317A1-20130704-T00171
Please refer to the end of the specification for access instructions.

TABLE-US-00175
Lengthy table referenced here
US20130172317A1-20130704-T00172
Please refer to the end of the specification for access instructions.

TABLE-US-00176
Lengthy table referenced here
US20130172317A1-20130704-T00173
Please refer to the end of the specification for access instructions.

TABLE-US-00177
Lengthy table referenced here
US20130172317A1-20130704-T00174
Please refer to the end of the specification for access instructions.

TABLE-US-00178
Lengthy table referenced here
US20130172317A1-20130704-T00175
Please refer to the end of the specification for access instructions.

TABLE-US-00179
Lengthy table referenced here
US20130172317A1-20130704-T00176
Please refer to the end of the specification for access instructions.

TABLE-US-00180
Lengthy table referenced here
US20130172317A1-20130704-T00177
Please refer to the end of the specification for access instructions.

TABLE-US-00181
Lengthy table referenced here
US20130172317A1-20130704-T00178
Please refer to the end of the specification for access instructions.

TABLE-US-00182
Lengthy table referenced here
US20130172317A1-20130704-T00179
Please refer to the end of the specification for access instructions.

TABLE-US-00183
Lengthy table referenced here
US20130172317A1-20130704-T00180
Please refer to the end of the specification for access instructions.

TABLE-US-00184
Lengthy table referenced here
US20130172317A1-20130704-T00181
Please refer to the end of the specification for access instructions.

TABLE-US-00185
Lengthy table referenced here
US20130172317A1-20130704-T00182
Please refer to the end of the specification for access instructions.

TABLE-US-00186
Lengthy table referenced here
US20130172317A1-20130704-T00183
Please refer to the end of the specification for access instructions.

TABLE-US-00187
Lengthy table referenced here
US20130172317A1-20130704-T00184
Please refer to the end of the specification for access instructions.

TABLE-US-00188
Lengthy table referenced here
US20130172317A1-20130704-T00185
Please refer to the end of the specification for access instructions.

TABLE-US-00189
Lengthy table referenced here
US20130172317A1-20130704-T00186
Please refer to the end of the specification for access instructions.

TABLE-US-00190
Lengthy table referenced here
US20130172317A1-20130704-T00187
Please refer to the end of the specification for access instructions.

TABLE-US-00191
Lengthy table referenced here
US20130172317A1-20130704-T00188
Please refer to the end of the specification for access instructions.

TABLE-US-00192
Lengthy table referenced here
US20130172317A1-20130704-T00189
Please refer to the end of the specification for access instructions.

TABLE-US-00193
Lengthy table referenced here
US20130172317A1-20130704-T00190
Please refer to the end of the specification for access instructions.

TABLE-US-00194
Lengthy table referenced here
US20130172317A1-20130704-T00191
Please refer to the end of the specification for access instructions.

TABLE-US-00195
Lengthy table referenced here
US20130172317A1-20130704-T00192
Please refer to the end of the specification for access instructions.

TABLE-US-00196
Lengthy table referenced here
US20130172317A1-20130704-T00193
Please refer to the end of the specification for access instructions.

TABLE-US-00197
Lengthy table referenced here
US20130172317A1-20130704-T00194
Please refer to the end of the specification for access instructions.

TABLE-US-00198
Lengthy table referenced here
US20130172317A1-20130704-T00195
Please refer to the end of the specification for access instructions.

TABLE-US-00199
Lengthy table referenced here
US20130172317A1-20130704-T00196
Please refer to the end of the specification for access instructions.

TABLE-US-00200
Lengthy table referenced here
US20130172317A1-20130704-T00197
Please refer to the end of the specification for access instructions.

TABLE-US-00201
Lengthy table referenced here
US20130172317A1-20130704-T00198
Please refer to the end of the specification for access instructions.

TABLE-US-00202
Lengthy table referenced here
US20130172317A1-20130704-T00199
Please refer to the end of the specification for access instructions.

TABLE-US-00203
Lengthy table referenced here
US20130172317A1-20130704-T00200
Please refer to the end of the specification for access instructions.

TABLE-US-00204
Lengthy table referenced here
US20130172317A1-20130704-T00201
Please refer to the end of the specification for access instructions.

TABLE-US-00205
Lengthy table referenced here
US20130172317A1-20130704-T00202
Please refer to the end of the specification for access instructions.

TABLE-US-00206
Lengthy table referenced here
US20130172317A1-20130704-T00203
Please refer to the end of the specification for access instructions.

TABLE-US-00207
Lengthy table referenced here
US20130172317A1-20130704-T00204
Please refer to the end of the specification for access instructions.

TABLE-US-00208
Lengthy table referenced here
US20130172317A1-20130704-T00205
Please refer to the end of the specification for access instructions.

TABLE-US-00209
Lengthy table referenced here
US20130172317A1-20130704-T00206
Please refer to the end of the specification for access instructions.

TABLE-US-00210
Lengthy table referenced here
US20130172317A1-20130704-T00207
Please refer to the end of the specification for access instructions.

TABLE-US-00211
Lengthy table referenced here
US20130172317A1-20130704-T00208
Please refer to the end of the specification for access instructions.

TABLE-US-00212
Lengthy table referenced here
US20130172317A1-20130704-T00209
Please refer to the end of the specification for access instructions.

TABLE-US-00213
Lengthy table referenced here
US20130172317A1-20130704-T00210
Please refer to the end of the specification for access instructions.

TABLE-US-00214
Lengthy table referenced here
US20130172317A1-20130704-T00211
Please refer to the end of the specification for access instructions.

TABLE-US-00215
Lengthy table referenced here
US20130172317A1-20130704-T00212
Please refer to the end of the specification for access instructions.

TABLE-US-00216
Lengthy table referenced here
US20130172317A1-20130704-T00213
Please refer to the end of the specification for access instructions.

TABLE-US-00217
Lengthy table referenced here
US20130172317A1-20130704-T00214
Please refer to the end of the specification for access instructions.

TABLE-US-00218
Lengthy table referenced here
US20130172317A1-20130704-T00215
Please refer to the end of the specification for access instructions.

TABLE-US-00219
Lengthy table referenced here
US20130172317A1-20130704-T00216
Please refer to the end of the specification for access instructions.

TABLE-US-00220
Lengthy table referenced here
US20130172317A1-20130704-T00217
Please refer to the end of the specification for access instructions.

TABLE-US-00221
Lengthy table referenced here
US20130172317A1-20130704-T00218
Please refer to the end of the specification for access instructions.

TABLE-US-00222
Lengthy table referenced here
US20130172317A1-20130704-T00219
Please refer to the end of the specification for access instructions.

TABLE-US-00223
Lengthy table referenced here
US20130172317A1-20130704-T00220
Please refer to the end of the specification for access instructions.

TABLE-US-00224
Lengthy table referenced here
US20130172317A1-20130704-T00221
Please refer to the end of the specification for access instructions.

TABLE-US-00225
Lengthy table referenced here
US20130172317A1-20130704-T00222
Please refer to the end of the specification for access instructions.

TABLE-US-00226
Lengthy table referenced here
US20130172317A1-20130704-T00223
Please refer to the end of the specification for access instructions.

TABLE-US-00227
Lengthy table referenced here
US20130172317A1-20130704-T00224
Please refer to the end of the specification for access instructions.

TABLE-US-00228
Lengthy table referenced here
US20130172317A1-20130704-T00225
Please refer to the end of the specification for access instructions.

TABLE-US-00229
Lengthy table referenced here
US20130172317A1-20130704-T00226
Please refer to the end of the specification for access instructions.

TABLE-US-00230
Lengthy table referenced here
US20130172317A1-20130704-T00227
Please refer to the end of the specification for access instructions.

TABLE-US-00231
Lengthy table referenced here
US20130172317A1-20130704-T00228
Please refer to the end of the specification for access instructions.

TABLE-US-00232
Lengthy table referenced here
US20130172317A1-20130704-T00229
Please refer to the end of the specification for access instructions.

TABLE-US-00233
Lengthy table referenced here
US20130172317A1-20130704-T00230
Please refer to the end of the specification for access instructions.

TABLE-US-00234
Lengthy table referenced here
US20130172317A1-20130704-T00231
Please refer to the end of the specification for access instructions.

TABLE-US-00235
Lengthy table referenced here
US20130172317A1-20130704-T00232
Please refer to the end of the specification for access instructions.

TABLE-US-00236
Lengthy table referenced here
US20130172317A1-20130704-T00233
Please refer to the end of the specification for access instructions.

TABLE-US-00237
Lengthy table referenced here
US20130172317A1-20130704-T00234
Please refer to the end of the specification for access instructions.

TABLE-US-00238
Lengthy table referenced here
US20130172317A1-20130704-T00235
Please refer to the end of the specification for access instructions.

TABLE-US-00239
Lengthy table referenced here
US20130172317A1-20130704-T00236
Please refer to the end of the specification for access instructions.

TABLE-US-00240
Lengthy table referenced here
US20130172317A1-20130704-T00237
Please refer to the end of the specification for access instructions.

TABLE-US-00241
Lengthy table referenced here
US20130172317A1-20130704-T00238
Please refer to the end of the specification for access instructions.

TABLE-US-00242
Lengthy table referenced here
US20130172317A1-20130704-T00239
Please refer to the end of the specification for access instructions.

TABLE-US-00243
Lengthy table referenced here
US20130172317A1-20130704-T00240
Please refer to the end of the specification for access instructions.

TABLE-US-00244
Lengthy table referenced here
US20130172317A1-20130704-T00241
Please refer to the end of the specification for access instructions.

TABLE-US-00245
Lengthy table referenced here
US20130172317A1-20130704-T00242
Please refer to the end of the specification for access instructions.

TABLE-US-00246
Lengthy table referenced here
US20130172317A1-20130704-T00243
Please refer to the end of the specification for access instructions.

TABLE-US-00247
Lengthy table referenced here
US20130172317A1-20130704-T00244
Please refer to the end of the specification for access instructions.

TABLE-US-00248
Lengthy table referenced here
US20130172317A1-20130704-T00245
Please refer to the end of the specification for access instructions.

TABLE-US-00249
Lengthy table referenced here
US20130172317A1-20130704-T00246
Please refer to the end of the specification for access instructions.

TABLE-US-00250
Lengthy table referenced here
US20130172317A1-20130704-T00247
Please refer to the end of the specification for access instructions.

TABLE-US-00251
Lengthy table referenced here
US20130172317A1-20130704-T00248
Please refer to the end of the specification for access instructions.

TABLE-US-00252
Lengthy table referenced here
US20130172317A1-20130704-T00249
Please refer to the end of the specification for access instructions.

TABLE-US-00253
Lengthy table referenced here
US20130172317A1-20130704-T00250
Please refer to the end of the specification for access instructions.

TABLE-US-00254
Lengthy table referenced here
US20130172317A1-20130704-T00251
Please refer to the end of the specification for access instructions.

TABLE-US-00255
Lengthy table referenced here
US20130172317A1-20130704-T00252
Please refer to the end of the specification for access instructions.

TABLE-US-00256
Lengthy table referenced here
US20130172317A1-20130704-T00253
Please refer to the end of the specification for access instructions.

TABLE-US-00257
Lengthy table referenced here
US20130172317A1-20130704-T00254
Please refer to the end of the specification for access instructions.

TABLE-US-00258
Lengthy table referenced here
US20130172317A1-20130704-T00255
Please refer to the end of the specification for access instructions.

TABLE-US-00259
Lengthy table referenced here
US20130172317A1-20130704-T00256
Please refer to the end of the specification for access instructions.

TABLE-US-00260
Lengthy table referenced here
US20130172317A1-20130704-T00257
Please refer to the end of the specification for access instructions.

TABLE-US-00261
Lengthy table referenced here
US20130172317A1-20130704-T00258
Please refer to the end of the specification for access instructions.

TABLE-US-00262
Lengthy table referenced here
US20130172317A1-20130704-T00259
Please refer to the end of the specification for access instructions.

TABLE-US-00263
Lengthy table referenced here
US20130172317A1-20130704-T00260
Please refer to the end of the specification for access instructions.

TABLE-US-00264
Lengthy table referenced here
US20130172317A1-20130704-T00261
Please refer to the end of the specification for access instructions.

TABLE-US-00265
Lengthy table referenced here
US20130172317A1-20130704-T00262
Please refer to the end of the specification for access instructions.

TABLE-US-00266
Lengthy table referenced here
US20130172317A1-20130704-T00263
Please refer to the end of the specification for access instructions.

TABLE-US-00267
Lengthy table referenced here
US20130172317A1-20130704-T00264
Please refer to the end of the specification for access instructions.

TABLE-US-00268
Lengthy table referenced here
US20130172317A1-20130704-T00265
Please refer to the end of the specification for access instructions.

TABLE-US-00269
Lengthy table referenced here
US20130172317A1-20130704-T00266
Please refer to the end of the specification for access instructions.

TABLE-US-00270
Lengthy table referenced here
US20130172317A1-20130704-T00267
Please refer to the end of the specification for access instructions.

TABLE-US-00271
Lengthy table referenced here
US20130172317A1-20130704-T00268
Please refer to the end of the specification for access instructions.

TABLE-US-00272
Lengthy table referenced here
US20130172317A1-20130704-T00269
Please refer to the end of the specification for access instructions.

TABLE-US-00273
Lengthy table referenced here
US20130172317A1-20130704-T00270
Please refer to the end of the specification for access instructions.

TABLE-US-00274
Lengthy table referenced here
US20130172317A1-20130704-T00271
Please refer to the end of the specification for access instructions.

TABLE-US-00275
Lengthy table referenced here
US20130172317A1-20130704-T00272
Please refer to the end of the specification for access instructions.

TABLE-US-00276
Lengthy table referenced here
US20130172317A1-20130704-T00273
Please refer to the end of the specification for access instructions.

TABLE-US-00277
Lengthy table referenced here
US20130172317A1-20130704-T00274
Please refer to the end of the specification for access instructions.

TABLE-US-00278
Lengthy table referenced here
US20130172317A1-20130704-T00275
Please refer to the end of the specification for access instructions.

TABLE-US-00279
Lengthy table referenced here
US20130172317A1-20130704-T00276
Please refer to the end of the specification for access instructions.

TABLE-US-00280
Lengthy table referenced here
US20130172317A1-20130704-T00277
Please refer to the end of the specification for access instructions.

TABLE-US-00281
Lengthy table referenced here
US20130172317A1-20130704-T00278
Please refer to the end of the specification for access instructions.

TABLE-US-00282
Lengthy table referenced here
US20130172317A1-20130704-T00279
Please refer to the end of the specification for access instructions.

TABLE-US-00283
Lengthy table referenced here
US20130172317A1-20130704-T00280
Please refer to the end of the specification for access instructions.

TABLE-US-00284
Lengthy table referenced here
US20130172317A1-20130704-T00281
Please refer to the end of the specification for access instructions.

TABLE-US-00285
Lengthy table referenced here
US20130172317A1-20130704-T00282
Please refer to the end of the specification for access instructions.

TABLE-US-00286
Lengthy table referenced here
US20130172317A1-20130704-T00283
Please refer to the end of the specification for access instructions.

TABLE-US-00287
Lengthy table referenced here
US20130172317A1-20130704-T00284
Please refer to the end of the specification for access instructions.

TABLE-US-00288
Lengthy table referenced here
US20130172317A1-20130704-T00285
Please refer to the end of the specification for access instructions.

TABLE-US-00289
Lengthy table referenced here
US20130172317A1-20130704-T00286
Please refer to the end of the specification for access instructions.

TABLE-US-00290
Lengthy table referenced here
US20130172317A1-20130704-T00287
Please refer to the end of the specification for access instructions.

TABLE-US-00291
Lengthy table referenced here
US20130172317A1-20130704-T00288
Please refer to the end of the specification for access instructions.

TABLE-US-00292
Lengthy table referenced here
US20130172317A1-20130704-T00289
Please refer to the end of the specification for access instructions.

TABLE-US-00293
Lengthy table referenced here
US20130172317A1-20130704-T00290
Please refer to the end of the specification for access instructions.

TABLE-US-00294
Lengthy table referenced here
US20130172317A1-20130704-T00291
Please refer to the end of the specification for access instructions.

TABLE-US-00295
Lengthy table referenced here
US20130172317A1-20130704-T00292
Please refer to the end of the specification for access instructions.

TABLE-US-00296
Lengthy table referenced here
US20130172317A1-20130704-T00293
Please refer to the end of the specification for access instructions.

TABLE-US-00297
Lengthy table referenced here
US20130172317A1-20130704-T00294
Please refer to the end of the specification for access instructions.

TABLE-US-00298
Lengthy table referenced here
US20130172317A1-20130704-T00295
Please refer to the end of the specification for access instructions.

TABLE-US-00299
Lengthy table referenced here
US20130172317A1-20130704-T00296
Please refer to the end of the specification for access instructions.

TABLE-US-00300
Lengthy table referenced here
US20130172317A1-20130704-T00297
Please refer to the end of the specification for access instructions.

TABLE-US-00301
Lengthy table referenced here
US20130172317A1-20130704-T00298
Please refer to the end of the specification for access instructions.

TABLE-US-00302
Lengthy table referenced here
US20130172317A1-20130704-T00299
Please refer to the end of the specification for access instructions.

TABLE-US-00303
Lengthy table referenced here
US20130172317A1-20130704-T00300
Please refer to the end of the specification for access instructions.

TABLE-US-00304
Lengthy table referenced here
US20130172317A1-20130704-T00301
Please refer to the end of the specification for access instructions.

TABLE-US-00305
Lengthy table referenced here
US20130172317A1-20130704-T00302
Please refer to the end of the specification for access instructions.

TABLE-US-00306
Lengthy table referenced here
US20130172317A1-20130704-T00303
Please refer to the end of the specification for access instructions.

TABLE-US-00307
Lengthy table referenced here
US20130172317A1-20130704-T00304
Please refer to the end of the specification for access instructions.

TABLE-US-00308
Lengthy table referenced here
US20130172317A1-20130704-T00305
Please refer to the end of the specification for access instructions.

TABLE-US-00309
Lengthy table referenced here
US20130172317A1-20130704-T00306
Please refer to the end of the specification for access instructions.

TABLE-US-00310
Lengthy table referenced here
US20130172317A1-20130704-T00307
Please refer to the end of the specification for access instructions.

TABLE-US-00311
Lengthy table referenced here
US20130172317A1-20130704-T00308
Please refer to the end of the specification for access instructions.

TABLE-US-00312
Lengthy table referenced here
US20130172317A1-20130704-T00309
Please refer to the end of the specification for access instructions.

TABLE-US-00313
Lengthy table referenced here
US20130172317A1-20130704-T00310
Please refer to the end of the specification for access instructions.

TABLE-US-00314
Lengthy table referenced here
US20130172317A1-20130704-T00311
Please refer to the end of the specification for access instructions.

TABLE-US-00315
Lengthy table referenced here
US20130172317A1-20130704-T00312
Please refer to the end of the specification for access instructions.

TABLE-US-00316
Lengthy table referenced here
US20130172317A1-20130704-T00313
Please refer to the end of the specification for access instructions.

TABLE-US-00317
Lengthy table referenced here
US20130172317A1-20130704-T00314
Please refer to the end of the specification for access instructions.

TABLE-US-00318
Lengthy table referenced here
US20130172317A1-20130704-T00315
Please refer to the end of the specification for access instructions.

TABLE-US-00319
Lengthy table referenced here
US20130172317A1-20130704-T00316
Please refer to the end of the specification for access instructions.

TABLE-US-00320
Lengthy table referenced here
US20130172317A1-20130704-T00317
Please refer to the end of the specification for access instructions.

TABLE-US-00321
Lengthy table referenced here
US20130172317A1-20130704-T00318
Please refer to the end of the specification for access instructions.

TABLE-US-00322
Lengthy table referenced here
US20130172317A1-20130704-T00319
Please refer to the end of the specification for access instructions.

TABLE-US-00323
Lengthy table referenced here
US20130172317A1-20130704-T00320
Please refer to the end of the specification for access instructions.

TABLE-US-00324
Lengthy table referenced here
US20130172317A1-20130704-T00321
Please refer to the end of the specification for access instructions.

TABLE-US-00325
Lengthy table referenced here
US20130172317A1-20130704-T00322
Please refer to the end of the specification for access instructions.

TABLE-US-00326
Lengthy table referenced here
US20130172317A1-20130704-T00323
Please refer to the end of the specification for access instructions.

TABLE-US-00327
Lengthy table referenced here
US20130172317A1-20130704-T00324
Please refer to the end of the specification for access instructions.

TABLE-US-00328
Lengthy table referenced here
US20130172317A1-20130704-T00325
Please refer to the end of the specification for access instructions.

TABLE-US-00329
Lengthy table referenced here
US20130172317A1-20130704-T00326
Please refer to the end of the specification for access instructions.

TABLE-US-00330
Lengthy table referenced here
US20130172317A1-20130704-T00327
Please refer to the end of the specification for access instructions.

TABLE-US-00331
Lengthy table referenced here
US20130172317A1-20130704-T00328
Please refer to the end of the specification for access instructions.

TABLE-US-00332
Lengthy table referenced here
US20130172317A1-20130704-T00329
Please refer to the end of the specification for access instructions.

TABLE-US-00333
Lengthy table referenced here
US20130172317A1-20130704-T00330
Please refer to the end of the specification for access instructions.

TABLE-US-00334
Lengthy table referenced here
US20130172317A1-20130704-T00331
Please refer to the end of the specification for access instructions.

TABLE-US-00335
Lengthy table referenced here
US20130172317A1-20130704-T00332
Please refer to the end of the specification for access instructions.

TABLE-US-00336
Lengthy table referenced here
US20130172317A1-20130704-T00333
Please refer to the end of the specification for access instructions.

TABLE-US-00337
Lengthy table referenced here
US20130172317A1-20130704-T00334
Please refer to the end of the specification for access instructions.

TABLE-US-00338
Lengthy table referenced here
US20130172317A1-20130704-T00335
Please refer to the end of the specification for access instructions.

TABLE-US-00339
Lengthy table referenced here
US20130172317A1-20130704-T00336
Please refer to the end of the specification for access instructions.

TABLE-US-00340
Lengthy table referenced here
US20130172317A1-20130704-T00337
Please refer to the end of the specification for access instructions.

TABLE-US-00341
Lengthy table referenced here
US20130172317A1-20130704-T00338
Please refer to the end of the specification for access instructions.

TABLE-US-00342
Lengthy table referenced here
US20130172317A1-20130704-T00339
Please refer to the end of the specification for access instructions.

TABLE-US-00343
Lengthy table referenced here
US20130172317A1-20130704-T00340
Please refer to the end of the specification for access instructions.

TABLE-US-00344
Lengthy table referenced here
US20130172317A1-20130704-T00341
Please refer to the end of the specification for access instructions.

TABLE-US-00345
Lengthy table referenced here
US20130172317A1-20130704-T00342
Please refer to the end of the specification for access instructions.

TABLE-US-00346
Lengthy table referenced here
US20130172317A1-20130704-T00343
Please refer to the end of the specification for access instructions.

TABLE-US-00347
Lengthy table referenced here
US20130172317A1-20130704-T00344
Please refer to the end of the specification for access instructions.

TABLE-US-00348
Lengthy table referenced here
US20130172317A1-20130704-T00345
Please refer to the end of the specification for access instructions.

TABLE-US-00349
Lengthy table referenced here
US20130172317A1-20130704-T00346
Please refer to the end of the specification for access instructions.

TABLE-US-00350
Lengthy table referenced here
US20130172317A1-20130704-T00347
Please refer to the end of the specification for access instructions.

TABLE-US-00351
Lengthy table referenced here
US20130172317A1-20130704-T00348
Please refer to the end of the specification for access instructions.

TABLE-US-00352
Lengthy table referenced here
US20130172317A1-20130704-T00349
Please refer to the end of the specification for access instructions.

TABLE-US-00353
Lengthy table referenced here
US20130172317A1-20130704-T00350
Please refer to the end of the specification for access instructions.

TABLE-US-00354
Lengthy table referenced here
US20130172317A1-20130704-T00351
Please refer to the end of the specification for access instructions.

TABLE-US-00355
Lengthy table referenced here
US20130172317A1-20130704-T00352
Please refer to the end of the specification for access instructions.

TABLE-US-00356
Lengthy table referenced here
US20130172317A1-20130704-T00353
Please refer to the end of the specification for access instructions.

TABLE-US-00357
Lengthy table referenced here
US20130172317A1-20130704-T00354
Please refer to the end of the specification for access instructions.

TABLE-US-00358
Lengthy table referenced here
US20130172317A1-20130704-T00355
Please refer to the end of the specification for access instructions.

TABLE-US-00359
Lengthy table referenced here
US20130172317A1-20130704-T00356
Please refer to the end of the specification for access instructions.

TABLE-US-00360
Lengthy table referenced here
US20130172317A1-20130704-T00357
Please refer to the end of the specification for access instructions.

TABLE-US-00361
Lengthy table referenced here
US20130172317A1-20130704-T00358
Please refer to the end of the specification for access instructions.

TABLE-US-00362
Lengthy table referenced here
US20130172317A1-20130704-T00359
Please refer to the end of the specification for access instructions.

TABLE-US-00363
Lengthy table referenced here
US20130172317A1-20130704-T00360
Please refer to the end of the specification for access instructions.

TABLE-US-00364
Lengthy table referenced here
US20130172317A1-20130704-T00361
Please refer to the end of the specification for access instructions.

TABLE-US-00365
Lengthy table referenced here
US20130172317A1-20130704-T00362
Please refer to the end of the specification for access instructions.

TABLE-US-00366
Lengthy table referenced here
US20130172317A1-20130704-T00363
Please refer to the end of the specification for access instructions.

TABLE-US-00367
Lengthy table referenced here
US20130172317A1-20130704-T00364
Please refer to the end of the specification for access instructions.

TABLE-US-00368
Lengthy table referenced here
US20130172317A1-20130704-T00365
Please refer to the end of the specification for access instructions.

TABLE-US-00369
Lengthy table referenced here
US20130172317A1-20130704-T00366
Please refer to the end of the specification for access instructions.

TABLE-US-00370
Lengthy table referenced here
US20130172317A1-20130704-T00367
Please refer to the end of the specification for access instructions.

TABLE-US-00371
Lengthy table referenced here
US20130172317A1-20130704-T00368
Please refer to the end of the specification for access instructions.

TABLE-US-00372
Lengthy table referenced here
US20130172317A1-20130704-T00369
Please refer to the end of the specification for access instructions.

TABLE-US-00373
Lengthy table referenced here
US20130172317A1-20130704-T00370
Please refer to the end of the specification for access instructions.

TABLE-US-00374
Lengthy table referenced here
US20130172317A1-20130704-T00371
Please refer to the end of the specification for access instructions.

TABLE-US-00375
Lengthy table referenced here
US20130172317A1-20130704-T00372
Please refer to the end of the specification for access instructions.

TABLE-US-00376
Lengthy table referenced here
US20130172317A1-20130704-T00373
Please refer to the end of the specification for access instructions.

TABLE-US-00377
Lengthy table referenced here
US20130172317A1-20130704-T00374
Please refer to the end of the specification for access instructions.

TABLE-US-00378
Lengthy table referenced here
US20130172317A1-20130704-T00375
Please refer to the end of the specification for access instructions.

TABLE-US-00379
Lengthy table referenced here
US20130172317A1-20130704-T00376
Please refer to the end of the specification for access instructions.

TABLE-US-00380
Lengthy table referenced here
US20130172317A1-20130704-T00377
Please refer to the end of the specification for access instructions.

TABLE-US-00381
Lengthy table referenced here
US20130172317A1-20130704-T00378
Please refer to the end of the specification for access instructions.

TABLE-US-00382
Lengthy table referenced here
US20130172317A1-20130704-T00379
Please refer to the end of the specification for access instructions.

TABLE-US-00383
Lengthy table referenced here
US20130172317A1-20130704-T00380
Please refer to the end of the specification for access instructions.

TABLE-US-00384
Lengthy table referenced here
US20130172317A1-20130704-T00381
Please refer to the end of the specification for access instructions.

TABLE-US-00385
Lengthy table referenced here
US20130172317A1-20130704-T00382
Please refer to the end of the specification for access instructions.

TABLE-US-00386
Lengthy table referenced here
US20130172317A1-20130704-T00383
Please refer to the end of the specification for access instructions.

TABLE-US-00387
Lengthy table referenced here
US20130172317A1-20130704-T00384
Please refer to the end of the specification for access instructions.

TABLE-US-00388
Lengthy table referenced here
US20130172317A1-20130704-T00385
Please refer to the end of the specification for access instructions.

TABLE-US-00389
Lengthy table referenced here
US20130172317A1-20130704-T00386
Please refer to the end of the specification for access instructions.

TABLE-US-00390
Lengthy table referenced here
US20130172317A1-20130704-T00387
Please refer to the end of the specification for access instructions.

TABLE-US-00391
Lengthy table referenced here
US20130172317A1-20130704-T00388
Please refer to the end of the specification for access instructions.

TABLE-US-00392
Lengthy table referenced here
US20130172317A1-20130704-T00389
Please refer to the end of the specification for access instructions.

TABLE-US-00393
Lengthy table referenced here
US20130172317A1-20130704-T00390
Please refer to the end of the specification for access instructions.

TABLE-US-00394
Lengthy table referenced here
US20130172317A1-20130704-T00391
Please refer to the end of the specification for access instructions.

TABLE-US-00395
Lengthy table referenced here
US20130172317A1-20130704-T00392
Please refer to the end of the specification for access instructions.

TABLE-US-00396
Lengthy table referenced here
US20130172317A1-20130704-T00393
Please refer to the end of the specification for access instructions.

TABLE-US-00397
Lengthy table referenced here
US20130172317A1-20130704-T00394
Please refer to the end of the specification for access instructions.

TABLE-US-00398
Lengthy table referenced here
US20130172317A1-20130704-T00395
Please refer to the end of the specification for access instructions.

TABLE-US-00399
Lengthy table referenced here
US20130172317A1-20130704-T00396
Please refer to the end of the specification for access instructions.

TABLE-US-00400
Lengthy table referenced here
US20130172317A1-20130704-T00397
Please refer to the end of the specification for access instructions.

TABLE-US-00401
Lengthy table referenced here
US20130172317A1-20130704-T00398
Please refer to the end of the specification for access instructions.

TABLE-US-00402
Lengthy table referenced here
US20130172317A1-20130704-T00399
Please refer to the end of the specification for access instructions.

TABLE-US-00403
Lengthy table referenced here
US20130172317A1-20130704-T00400
Please refer to the end of the specification for access instructions.

TABLE-US-00404
Lengthy table referenced here
US20130172317A1-20130704-T00401
Please refer to the end of the specification for access instructions.

TABLE-US-00405
Lengthy table referenced here
US20130172317A1-20130704-T00402
Please refer to the end of the specification for access instructions.

TABLE-US-00406
Lengthy table referenced here
US20130172317A1-20130704-T00403
Please refer to the end of the specification for access instructions.

TABLE-US-00407
Lengthy table referenced here
US20130172317A1-20130704-T00404
Please refer to the end of the specification for access instructions.

TABLE-US-00408
Lengthy table referenced here
US20130172317A1-20130704-T00405
Please refer to the end of the specification for access instructions.

TABLE-US-00409
Lengthy table referenced here
US20130172317A1-20130704-T00406
Please refer to the end of the specification for access instructions.

TABLE-US-00410
Lengthy table referenced here
US20130172317A1-20130704-T00407
Please refer to the end of the specification for access instructions.

TABLE-US-00411
Lengthy table referenced here
US20130172317A1-20130704-T00408
Please refer to the end of the specification for access instructions.

TABLE-US-00412
Lengthy table referenced here
US20130172317A1-20130704-T00409
Please refer to the end of the specification for access instructions.

TABLE-US-00413
Lengthy table referenced here
US20130172317A1-20130704-T00410
Please refer to the end of the specification for access instructions.

TABLE-US-00414
Lengthy table referenced here
US20130172317A1-20130704-T00411
Please refer to the end of the specification for access instructions.

TABLE-US-00415
Lengthy table referenced here
US20130172317A1-20130704-T00412
Please refer to the end of the specification for access instructions.

TABLE-US-00416
Lengthy table referenced here
US20130172317A1-20130704-T00413
Please refer to the end of the specification for access instructions.

TABLE-US-00417
Lengthy table referenced here
US20130172317A1-20130704-T00414
Please refer to the end of the specification for access instructions.

TABLE-US-00418
Lengthy table referenced here
US20130172317A1-20130704-T00415
Please refer to the end of the specification for access instructions.

TABLE-US-00419
Lengthy table referenced here
US20130172317A1-20130704-T00416
Please refer to the end of the specification for access instructions.

TABLE-US-00420
Lengthy table referenced here
US20130172317A1-20130704-T00417
Please refer to the end of the specification for access instructions.

TABLE-US-00421
Lengthy table referenced here
US20130172317A1-20130704-T00418
Please refer to the end of the specification for access instructions.

TABLE-US-00422
Lengthy table referenced here
US20130172317A1-20130704-T00419
Please refer to the end of the specification for access instructions.

TABLE-US-00423
Lengthy table referenced here
US20130172317A1-20130704-T00420
Please refer to the end of the specification for access instructions.

TABLE-US-00424
Lengthy table referenced here
US20130172317A1-20130704-T00421
Please refer to the end of the specification for access instructions.

TABLE-US-00425
Lengthy table referenced here
US20130172317A1-20130704-T00422
Please refer to the end of the specification for access instructions.

TABLE-US-00426
Lengthy table referenced here
US20130172317A1-20130704-T00423
Please refer to the end of the specification for access instructions.

TABLE-US-00427
Lengthy table referenced here
US20130172317A1-20130704-T00424
Please refer to the end of the specification for access instructions.

TABLE-US-00428
Lengthy table referenced here
US20130172317A1-20130704-T00425
Please refer to the end of the specification for access instructions.

TABLE-US-00429
Lengthy table referenced here
US20130172317A1-20130704-T00426
Please refer to the end of the specification for access instructions.

TABLE-US-00430
Lengthy table referenced here
US20130172317A1-20130704-T00427
Please refer to the end of the specification for access instructions.

TABLE-US-00431
Lengthy table referenced here
US20130172317A1-20130704-T00428
Please refer to the end of the specification for access instructions.

TABLE-US-00432
Lengthy table referenced here
US20130172317A1-20130704-T00429
Please refer to the end of the specification for access instructions.

TABLE-US-00433
Lengthy table referenced here
US20130172317A1-20130704-T00430
Please refer to the end of the specification for access instructions.

TABLE-US-00434
Lengthy table referenced here
US20130172317A1-20130704-T00431
Please refer to the end of the specification for access instructions.

TABLE-US-00435
Lengthy table referenced here
US20130172317A1-20130704-T00432
Please refer to the end of the specification for access instructions.

TABLE-US-00436
Lengthy table referenced here
US20130172317A1-20130704-T00433
Please refer to the end of the specification for access instructions.

TABLE-US-00437
Lengthy table referenced here
US20130172317A1-20130704-T00434
Please refer to the end of the specification for access instructions.

TABLE-US-00438
Lengthy table referenced here
US20130172317A1-20130704-T00435
Please refer to the end of the specification for access instructions.

TABLE-US-00439
Lengthy table referenced here
US20130172317A1-20130704-T00436
Please refer to the end of the specification for access instructions.

TABLE-US-00440
Lengthy table referenced here
US20130172317A1-20130704-T00437
Please refer to the end of the specification for access instructions.

TABLE-US-00441
Lengthy table referenced here
US20130172317A1-20130704-T00438
Please refer to the end of the specification for access instructions.

TABLE-US-00442
Lengthy table referenced here
US20130172317A1-20130704-T00439
Please refer to the end of the specification for access instructions.

TABLE-US-00443
Lengthy table referenced here
US20130172317A1-20130704-T00440
Please refer to the end of the specification for access instructions.

TABLE-US-00444
Lengthy table referenced here
US20130172317A1-20130704-T00441
Please refer to the end of the specification for access instructions.

TABLE-US-00445
Lengthy table referenced here
US20130172317A1-20130704-T00442
Please refer to the end of the specification for access instructions.

TABLE-US-00446
Lengthy table referenced here
US20130172317A1-20130704-T00443
Please refer to the end of the specification for access instructions.

TABLE-US-00447
Lengthy table referenced here
US20130172317A1-20130704-T00444
Please refer to the end of the specification for access instructions.

TABLE-US-00448
Lengthy table referenced here
US20130172317A1-20130704-T00445
Please refer to the end of the specification for access instructions.

TABLE-US-00449
Lengthy table referenced here
US20130172317A1-20130704-T00446
Please refer to the end of the specification for access instructions.

TABLE-US-00450
Lengthy table referenced here
US20130172317A1-20130704-T00447
Please refer to the end of the specification for access instructions.

TABLE-US-00451
Lengthy table referenced here
US20130172317A1-20130704-T00448
Please refer to the end of the specification for access instructions.

TABLE-US-00452
Lengthy table referenced here
US20130172317A1-20130704-T00449
Please refer to the end of the specification for access instructions.

TABLE-US-00453
Lengthy table referenced here
US20130172317A1-20130704-T00450
Please refer to the end of the specification for access instructions.

TABLE-US-00454
Lengthy table referenced here
US20130172317A1-20130704-T00451
Please refer to the end of the specification for access instructions.

TABLE-US-00455
Lengthy table referenced here
US20130172317A1-20130704-T00452
Please refer to the end of the specification for access instructions.

TABLE-US-00456
Lengthy table referenced here
US20130172317A1-20130704-T00453
Please refer to the end of the specification for access instructions.

TABLE-US-00457
Lengthy table referenced here
US20130172317A1-20130704-T00454
Please refer to the end of the specification for access instructions.

TABLE-US-00458
Lengthy table referenced here
US20130172317A1-20130704-T00455
Please refer to the end of the specification for access instructions.

TABLE-US-00459
Lengthy table referenced here
US20130172317A1-20130704-T00456
Please refer to the end of the specification for access instructions.

TABLE-US-00460
Lengthy table referenced here
US20130172317A1-20130704-T00457
Please refer to the end of the specification for access instructions.

TABLE-US-00461
Lengthy table referenced here
US20130172317A1-20130704-T00458
Please refer to the end of the specification for access instructions.

TABLE-US-00462
Lengthy table referenced here
US20130172317A1-20130704-T00459
Please refer to the end of the specification for access instructions.

TABLE-US-00463
Lengthy table referenced here
US20130172317A1-20130704-T00460
Please refer to the end of the specification for access instructions.

TABLE-US-00464
Lengthy table referenced here
US20130172317A1-20130704-T00461
Please refer to the end of the specification for access instructions.

TABLE-US-00465
Lengthy table referenced here
US20130172317A1-20130704-T00462
Please refer to the end of the specification for access instructions.

TABLE-US-00466
Lengthy table referenced here
US20130172317A1-20130704-T00463
Please refer to the end of the specification for access instructions.

TABLE-US-00467
Lengthy table referenced here
US20130172317A1-20130704-T00464
Please refer to the end of the specification for access instructions.

TABLE-US-00468
Lengthy table referenced here
US20130172317A1-20130704-T00465
Please refer to the end of the specification for access instructions.

TABLE-US-00469
Lengthy table referenced here
US20130172317A1-20130704-T00466
Please refer to the end of the specification for access instructions.

TABLE-US-00470
Lengthy table referenced here
US20130172317A1-20130704-T00467
Please refer to the end of the specification for access instructions.

TABLE-US-00471
Lengthy table referenced here
US20130172317A1-20130704-T00468
Please refer to the end of the specification for access instructions.

TABLE-US-00472
Lengthy table referenced here
US20130172317A1-20130704-T00469
Please refer to the end of the specification for access instructions.

TABLE-US-00473
Lengthy table referenced here
US20130172317A1-20130704-T00470
Please refer to the end of the specification for access instructions.

TABLE-US-00474
Lengthy table referenced here
US20130172317A1-20130704-T00471
Please refer to the end of the specification for access instructions.

TABLE-US-00475
Lengthy table referenced here
US20130172317A1-20130704-T00472
Please refer to the end of the specification for access instructions.

TABLE-US-00476
Lengthy table referenced here
US20130172317A1-20130704-T00473
Please refer to the end of the specification for access instructions.

TABLE-US-00477
Lengthy table referenced here
US20130172317A1-20130704-T00474
Please refer to the end of the specification for access instructions.

TABLE-US-00478
Lengthy table referenced here
US20130172317A1-20130704-T00475
Please refer to the end of the specification for access instructions.

TABLE-US-00479
Lengthy table referenced here
US20130172317A1-20130704-T00476
Please refer to the end of the specification for access instructions.

TABLE-US-00480
Lengthy table referenced here
US20130172317A1-20130704-T00477
Please refer to the end of the specification for access instructions.

TABLE-US-00481
Lengthy table referenced here
US20130172317A1-20130704-T00478
Please refer to the end of the specification for access instructions.

TABLE-US-00482
Lengthy table referenced here
US20130172317A1-20130704-T00479
Please refer to the end of the specification for access instructions.

TABLE-US-00483
Lengthy table referenced here
US20130172317A1-20130704-T00480
Please refer to the end of the specification for access instructions.

TABLE-US-00484
Lengthy table referenced here
US20130172317A1-20130704-T00481
Please refer to the end of the specification for access instructions.

TABLE-US-00485
Lengthy table referenced here
US20130172317A1-20130704-T00482
Please refer to the end of the specification for access instructions.

TABLE-US-00486
Lengthy table referenced here
US20130172317A1-20130704-T00483
Please refer to the end of the specification for access instructions.

TABLE-US-00487
Lengthy table referenced here
US20130172317A1-20130704-T00484
Please refer to the end of the specification for access instructions.

TABLE-US-00488
Lengthy table referenced here
US20130172317A1-20130704-T00485
Please refer to the end of the specification for access instructions.

TABLE-US-00489
Lengthy table referenced here
US20130172317A1-20130704-T00486
Please refer to the end of the specification for access instructions.

TABLE-US-00490
Lengthy table referenced here
US20130172317A1-20130704-T00487
Please refer to the end of the specification for access instructions.

TABLE-US-00491
Lengthy table referenced here
US20130172317A1-20130704-T00488
Please refer to the end of the specification for access instructions.

TABLE-US-00492
Lengthy table referenced here
US20130172317A1-20130704-T00489
Please refer to the end of the specification for access instructions.

TABLE-US-00493
Lengthy table referenced here
US20130172317A1-20130704-T00490
Please refer to the end of the specification for access instructions.

TABLE-US-00494
Lengthy table referenced here
US20130172317A1-20130704-T00491
Please refer to the end of the specification for access instructions.

TABLE-US-00495
Lengthy table referenced here
US20130172317A1-20130704-T00492
Please refer to the end of the specification for access instructions.

TABLE-US-00496
Lengthy table referenced here
US20130172317A1-20130704-T00493
Please refer to the end of the specification for access instructions.

TABLE-US-00497
Lengthy table referenced here
US20130172317A1-20130704-T00494
Please refer to the end of the specification for access instructions.

TABLE-US-00498
Lengthy table referenced here
US20130172317A1-20130704-T00495
Please refer to the end of the specification for access instructions.

TABLE-US-00499
Lengthy table referenced here
US20130172317A1-20130704-T00496
Please refer to the end of the specification for access instructions.

TABLE-US-00500
Lengthy table referenced here
US20130172317A1-20130704-T00497
Please refer to the end of the specification for access instructions.

TABLE-US-00501
Lengthy table referenced here
US20130172317A1-20130704-T00498
Please refer to the end of the specification for access instructions.

TABLE-US-00502
Lengthy table referenced here
US20130172317A1-20130704-T00499
Please refer to the end of the specification for access instructions.

TABLE-US-00503
Lengthy table referenced here
US20130172317A1-20130704-T00500
Please refer to the end of the specification for access instructions.

TABLE-US-00504
Lengthy table referenced here
US20130172317A1-20130704-T00501
Please refer to the end of the specification for access instructions.

TABLE-US-00505
Lengthy table referenced here
US20130172317A1-20130704-T00502
Please refer to the end of the specification for access instructions.

TABLE-US-00506
Lengthy table referenced here
US20130172317A1-20130704-T00503
Please refer to the end of the specification for access instructions.

TABLE-US-00507
Lengthy table referenced here
US20130172317A1-20130704-T00504
Please refer to the end of the specification for access instructions.

TABLE-US-00508
Lengthy table referenced here
US20130172317A1-20130704-T00505
Please refer to the end of the specification for access instructions.

TABLE-US-00509
Lengthy table referenced here
US20130172317A1-20130704-T00506
Please refer to the end of the specification for access instructions.

TABLE-US-00510
Lengthy table referenced here
US20130172317A1-20130704-T00507
Please refer to the end of the specification for access instructions.

TABLE-US-00511
Lengthy table referenced here
US20130172317A1-20130704-T00508
Please refer to the end of the specification for access instructions.

TABLE-US-00512
Lengthy table referenced here
US20130172317A1-20130704-T00509
Please refer to the end of the specification for access instructions.

TABLE-US-00513
Lengthy table referenced here
US20130172317A1-20130704-T00510
Please refer to the end of the specification for access instructions.

TABLE-US-00514
Lengthy table referenced here
US20130172317A1-20130704-T00511
Please refer to the end of the specification for access instructions.

TABLE-US-00515
Lengthy table referenced here
US20130172317A1-20130704-T00512
Please refer to the end of the specification for access instructions.

TABLE-US-00516
Lengthy table referenced here
US20130172317A1-20130704-T00513
Please refer to the end of the specification for access instructions.

TABLE-US-00517
Lengthy table referenced here
US20130172317A1-20130704-T00514
Please refer to the end of the specification for access instructions.

TABLE-US-00518
Lengthy table referenced here
US20130172317A1-20130704-T00515
Please refer to the end of the specification for access instructions.

TABLE-US-00519
Lengthy table referenced here
US20130172317A1-20130704-T00516
Please refer to the end of the specification for access instructions.

TABLE-US-00520
Lengthy table referenced here
US20130172317A1-20130704-T00517
Please refer to the end of the specification for access instructions.

TABLE-US-00521
Lengthy table referenced here
US20130172317A1-20130704-T00518
Please refer to the end of the specification for access instructions.

TABLE-US-00522
Lengthy table referenced here
US20130172317A1-20130704-T00519
Please refer to the end of the specification for access instructions.

TABLE-US-00523
Lengthy table referenced here
US20130172317A1-20130704-T00520
Please refer to the end of the specification for access instructions.

TABLE-US-00524
Lengthy table referenced here
US20130172317A1-20130704-T00521
Please refer to the end of the specification for access instructions.

TABLE-US-00525
Lengthy table referenced here
US20130172317A1-20130704-T00522
Please refer to the end of the specification for access instructions.

TABLE-US-00526
Lengthy table referenced here
US20130172317A1-20130704-T00523
Please refer to the end of the specification for access instructions.

TABLE-US-00527
Lengthy table referenced here
US20130172317A1-20130704-T00524
Please refer to the end of the specification for access instructions.

TABLE-US-00528
Lengthy table referenced here
US20130172317A1-20130704-T00525
Please refer to the end of the specification for access instructions.

TABLE-US-00529
Lengthy table referenced here
US20130172317A1-20130704-T00526
Please refer to the end of the specification for access instructions.

TABLE-US-00530
Lengthy table referenced here
US20130172317A1-20130704-T00527
Please refer to the end of the specification for access instructions.

TABLE-US-00531
Lengthy table referenced here
US20130172317A1-20130704-T00528
Please refer to the end of the specification for access instructions.

TABLE-US-00532
Lengthy table referenced here
US20130172317A1-20130704-T00529
Please refer to the end of the specification for access instructions.

TABLE-US-00533
Lengthy table referenced here
US20130172317A1-20130704-T00530
Please refer to the end of the specification for access instructions.

TABLE-US-00534
Lengthy table referenced here
US20130172317A1-20130704-T00531
Please refer to the end of the specification for access instructions.

TABLE-US-00535
Lengthy table referenced here
US20130172317A1-20130704-T00532
Please refer to the end of the specification for access instructions.

TABLE-US-00536
Lengthy table referenced here
US20130172317A1-20130704-T00533
Please refer to the end of the specification for access instructions.

TABLE-US-00537
Lengthy table referenced here
US20130172317A1-20130704-T00534
Please refer to the end of the specification for access instructions.

TABLE-US-00538
Lengthy table referenced here
US20130172317A1-20130704-T00535
Please refer to the end of the specification for access instructions.

TABLE-US-00539
Lengthy table referenced here
US20130172317A1-20130704-T00536
Please refer to the end of the specification for access instructions.

TABLE-US-00540
Lengthy table referenced here
US20130172317A1-20130704-T00537
Please refer to the end of the specification for access instructions.

TABLE-US-00541
Lengthy table referenced here
US20130172317A1-20130704-T00538
Please refer to the end of the specification for access instructions.

TABLE-US-00542
Lengthy table referenced here
US20130172317A1-20130704-T00539
Please refer to the end of the specification for access instructions.

TABLE-US-00543
Lengthy table referenced here
US20130172317A1-20130704-T00540
Please refer to the end of the specification for access instructions.

TABLE-US-00544
Lengthy table referenced here
US20130172317A1-20130704-T00541
Please refer to the end of the specification for access instructions.

TABLE-US-00545
Lengthy table referenced here
US20130172317A1-20130704-T00542
Please refer to the end of the specification for access instructions.

TABLE-US-00546
Lengthy table referenced here
US20130172317A1-20130704-T00543
Please refer to the end of the specification for access instructions.

TABLE-US-00547
Lengthy table referenced here
US20130172317A1-20130704-T00544
Please refer to the end of the specification for access instructions.

TABLE-US-00548
Lengthy table referenced here
US20130172317A1-20130704-T00545
Please refer to the end of the specification for access instructions.

TABLE-US-00549
Lengthy table referenced here
US20130172317A1-20130704-T00546
Please refer to the end of the specification for access instructions.

TABLE-US-00550
Lengthy table referenced here
US20130172317A1-20130704-T00547
Please refer to the end of the specification for access instructions.

TABLE-US-00551
Lengthy table referenced here
US20130172317A1-20130704-T00548
Please refer to the end of the specification for access instructions.

TABLE-US-00552
Lengthy table referenced here
US20130172317A1-20130704-T00549
Please refer to the end of the specification for access instructions.

TABLE-US-00553
Lengthy table referenced here
US20130172317A1-20130704-T00550
Please refer to the end of the specification for access instructions.

TABLE-US-00554
Lengthy table referenced here
US20130172317A1-20130704-T00551
Please refer to the end of the specification for access instructions.

TABLE-US-00555
Lengthy table referenced here
US20130172317A1-20130704-T00552
Please refer to the end of the specification for access instructions.

TABLE-US-00556
Lengthy table referenced here
US20130172317A1-20130704-T00553
Please refer to the end of the specification for access instructions.

TABLE-US-00557
Lengthy table referenced here
US20130172317A1-20130704-T00554
Please refer to the end of the specification for access instructions.

TABLE-US-00558
Lengthy table referenced here
US20130172317A1-20130704-T00555
Please refer to the end of the specification for access instructions.

TABLE-US-00559
Lengthy table referenced here
US20130172317A1-20130704-T00556
Please refer to the end of the specification for access instructions.

TABLE-US-00560
Lengthy table referenced here
US20130172317A1-20130704-T00557
Please refer to the end of the specification for access instructions.

TABLE-US-00561
Lengthy table referenced here
US20130172317A1-20130704-T00558
Please refer to the end of the specification for access instructions.

TABLE-US-00562
Lengthy table referenced here
US20130172317A1-20130704-T00559
Please refer to the end of the specification for access instructions.

TABLE-US-00563
Lengthy table referenced here
US20130172317A1-20130704-T00560
Please refer to the end of the specification for access instructions.

TABLE-US-00564
Lengthy table referenced here
US20130172317A1-20130704-T00561
Please refer to the end of the specification for access instructions.

TABLE-US-00565
Lengthy table referenced here
US20130172317A1-20130704-T00562
Please refer to the end of the specification for access instructions.

TABLE-US-00566
Lengthy table referenced here
US20130172317A1-20130704-T00563
Please refer to the end of the specification for access instructions.

TABLE-US-00567
Lengthy table referenced here
US20130172317A1-20130704-T00564
Please refer to the end of the specification for access instructions.

TABLE-US-00568
Lengthy table referenced here
US20130172317A1-20130704-T00565
Please refer to the end of the specification for access instructions.

Test Examples

Test Example 1

Evaluation of Human P2X3 Receptor Inhibitory Activity

[0883] Stably expressing cell line (C6BU-1 cell transfected with human
P2X3 receptor gene (GenBank accession number Y07683) was used. The
cells were seeded in a 96-well microtiter plate at a concentration of
8000 cells/well and cultured in the medium (8.3% fetal bovine serum, 8.3%
horse serum, 1% antibiotic and antifungal in DMEM) for one day at
37° C. under 5% carbon dioxide atmosphere. The medium was replaced
with 4 μM Fluo-3-AM solution (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl,
0.9 mM MgCl2, 5.0 mM CaCl2, 5.6 mM D-glucose, 2.5 mM
probenecid, 10% BSA, and 0.08% Pluronic F-127, pH 7.5) and incubated at
37° C. under 5% dioxide carbon atmosphere for one hour. The plate
was washed with washing buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9
mM MgCl2, 5.0 mM CaCl2, 5.6 mM D-glucose, 2.5 mM probenecid,
pH7.5), and each well was added with 40 μL of this buffer. The plate
was placed in High-Throughput Screening System FDSS 3000 (Hamamatsu
Photonics K.K.). Measurement of fluorescence intensity by FDSS 3000 was
started, and 40 μL of DMSO solutions containing different
concentrations of the test compound as prepared by dilution with dilution
buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl2, 5.0 mM
CaCl2, 5.6 mM D-glucose, 2.5 mM probenecid, 0.1% Pluronic F-127,
pH7.5) were dispensed to each well through the built-in automatic
dispenser. Five minutes after, 50 nM ATP solution (50 μL) prepared by
dilution with the dilution buffer was dispensed through the built-in
automatic dispenser, and the measurement of fluorescence intensity was
continued for 3 min. For each well, the specific maximum fluorescence
intensity was calculated as the ratio of the maximum fluorescence
intensity after addition of the ATP solution to the fluorescence
intensity at the starting of the measurement. The 50% inhibitory
concentration (IC50) was calculated under the assumption that the
specific maximum fluorescence intensity without test compound is 0%
inhibition and that the specific maximum fluorescence intensity when the
dilution buffer was added in place of ATP solution is 100% inhibition, to
evaluate the inhibitory activity of the test compound. FDSS software
(Hamamatsu Photonics K.K.) was used for calculation of the specific
maximum fluorescence intensity. IC50 was calculated using Microsoft
Excel (Microsoft Corporation) and XLfit (idbs Ltd.)

[0884] The data of the compounds of the present invention are as shown in
the following Tables.

[0885] Rat P2X3 receptor gene (GenBank accession number NM--031075)
was expressed in C6BU-1 cell. The cells stably expressing rat P2X3
were seeded in a 96-well microtiter plate at a concentration of 8000
cells/well and cultured in the medium (8.3% fetal bovine serum, 8.3%
horse serum, 1% antibiotic and antifungal in DMEM) for one day at
37° C. under 5% carbon dioxide atmosphere. In transiently
expressing system, the C6BU-1 cells were seeded in a 96-well microtiter
plate at a concentration of 2500 cells/well and cultured in the medium
for one day at 37° C. under 5% carbon dioxide atmosphere. The
plasmid was transfected into the cells using transfection reagent FuGENE6
(Roche). The transfected cells were cultured in the medium for one day at
37° C. under 5% carbon dioxide atmosphere. The medium was replaced
with 4 μM Fluo-3-AM solution (pH7.5) containing 20 mM HEPES, 137 mM
NaCl, 2.7 mM KCl, 0.9 mM MgCl2, 5.0 mM CaCl2, 5.6 mM D-glucose,
2.5 mM probenecid, 10% BSA, and 0.08% Pluronic F-127, and incubated at
37° C. under 5% dioxide carbon atmosphere for one hour. The plate
was washed with washing buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9
mM MgCl2, 5.0 mM CaCl, 5.6 mM D-glucose, 2.5 mM probenecid, pH7.5),
and each well was added with 40 μL of this buffer. The plate was
placed in High-Throughput Screening System FDSS 3000 (Hamamatsu Photonics
K.K.). Measurement of fluorescence intensity by FDSS 3000 was started,
and 40 μL of DMSO solutions containing different concentrations of the
test compound as prepared by dilution with dilution buffer (20 mM HEPES,
137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl2, 5.0 mM CaCl2, 5.6 mM
D-glucose, 2.5 mM probenecid, 0.1% Pluronic F-127, pH7.5) were dispensed
to each well through the built-in automatic dispenser. Five minutes
after, 50 nM ATP solution (50 μL) prepared by dilution with the
dilution buffer was dispensed through the built-in automatic dispenser,
and the measurement of fluorescence intensity was continued for 3 min.
For each well, the specific maximum fluorescence intensity was calculated
as the ratio of the maximum fluorescence intensity after addition of the
ATP solution to the fluorescence intensity at the starting of the
measurement. The 50% inhibitory concentration (IC50) was calculated
under the assumption that the specific maximum fluorescence intensity
without test compound is 0% inhibition and that the specific maximum
fluorescence intensity when the dilution buffer was added in place of ATP
solution is 100% inhibition, to evaluate the inhibitory activity of the
test compound. FDSS software (Hamamatsu Photonics K.K.) was used for
calculation of the specific maximum fluorescence intensity. IC50 was
calculated using Microsoft Excel (Microsoft Corporation) and XLfit (idbs
Ltd.).

[0886] The data of the compounds of the present invention are as shown in
the following Table.

[0887] Rat P2X3 receptor gene (GenBank accession number NM--031075)
was expressed in C6BU-1 cell. The cells stably expressing rat P2X3
were seeded in a 96-well microtiter plate at a concentration of 8000
cells/well and cultured in the medium (8.3% fetal bovine serum, 8.3%
horse serum, 1% antibiotic and antifungal in DMEM) for one day at
37° C. under 5% carbon dioxide atmosphere. In transiently
expressing system, the C6BU-1 cells were seeded in a 96-well microtiter
plate at a concentration of 2500 cells/well and cultured in the medium
for one day at 37° C. under 5% carbon dioxide atmosphere. The
plasmid was transfected into the cells using transfection reagent FuGENE6
(Roche). The transfected cells were cultured in the medium for one day at
37° C. under 5% carbon dioxide atmosphere. The medium was replaced
with 4 μM Fluo-3-AM solution (pH7.5) containing 20 mM HEPES, 137 mM
NaCl, 2.7 mM KCl, 0.9 mM MgCl2, 5.0 mM CaCl2, 5.6 mM D-glucose,
2.5 mM probenecid, 10% BSA, and 0.08% Pluronic F-127, and incubated at
37° C. under 5% carbon dioxide atmosphere for one hour. The plate
was washed with washing buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9
mM MgCl2, 5.0 mM CaCl2, 5.6 mM D-glucose, 2.5 mM probenecid,
pH7.5), and each well was added with 40 μL of this buffer. The plate
was placed in High-Throughput Screening System FDSS 3000 (Hamamatsu
Photonics K.K.). Measurement of fluorescence intensity by FDSS 3000 was
started, and 40 μL of DMSO solutions containing 1% RSA (final
concentrations) and different concentrations of the test compound as
prepared by dilution with dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7
mM KCl, 0.9 mM MgCl2, 5.0 mM CaCl2, 5.6 mM D-glucose, 2.5 mM
probenecid, 0.1% Pluronic F-127, pH7.5) were dispensed to each well
through the built-in automatic dispenser. Five minutes after, 50 nM ATP
solution (50 μL) prepared by dilution with the dilution buffer was
dispensed through the built-in automatic dispenser, and the measurement
of fluorescence intensity was continued for 3 min. For each well, the
specific maximum fluorescence intensity was calculated as the ratio of
the maximum fluorescence intensity after addition of the ATP solution to
the fluorescence intensity at the starting of the measurement. The 50%
inhibitory concentration (IC50) was calculated under the assumption
that the specific maximum fluorescence intensity without test compound is
0% inhibition and that the specific maximum fluorescence intensity when
the dilution buffer was added in place of ATP solution is 100%
inhibition, to evaluate the inhibitory activity of the test compound.
FDSS software (Hamamatsu Photonics K.K.) was used for calculation of the
specific maximum fluorescence intensity. IC50 was calculated using
Microsoft Excel (Microsoft Corporation) and XLfit (idbs Ltd.).

[0888] The data of the compounds of the present invention are as shown in
the following Table.

[0890] A rat was fixed in the supine position after being given anesthesia
through the inhalation of 2% isoflurane (Anesthetic background; Nitrous
oxide:Oxygen=7:3). A midline incision was made in its abdomen to expose
the bladder. A cannula (made by processing a polyethylene tube (PE-50:
Becton Dickinson)) was inserted through a small incision on top of the
bladder and fixed to create a bladder fistula. The other end of the
cannula was led through the hypodermal tissue to the back, and the
muscular coat and skin were sutured. The cannula, which was led to the
back, was protected with a stainless spring in the middle and connected
to the cannula swivel.

[0891] Acetic Acid Infusion

[0892] Two days after the surgery, 0.3% acetic acid was infused into the
bladder through the indwelled cannula at a rate of 4 mL/hr for 30 minutes
to induce cystitis. The animals, where acetic acid was not infused, were
used as normal animals.

[0893] Cystometry Measurement

[0894] Three days after the acetic acid infusion, the other end of the
cannula inserted into the bladder was connected to a T shape stopcock and
then the intravesical pressure was recorded continuously using a pressure
amplifier while infusing warmed normal saline solution at a rate of 3.0
mL/hr from one side and through a pressure transducer on the other side.
The baseline of the intravesical pressure was measured (for approximately
40 minutes) after a measurement for stable duration (for approximately
minutes). After that, a vehicle, positive control compound or test
compound were administered, and the value after administration was
measured for approximately 120 minutes. At the same time, the voided
urine was received on scales under the cage to measure the variation in
weight simultaneously.

[0895] Data Adoption Criteria

[0896] Based on the voiding interval, normal animals whose voiding
interval was 10 minutes or longer were adopted and those whose voiding
interval was shorter than that were excluded. In the case of the animals
into which acetic acid was infused, those whose voiding interval was less
than half the average value of the normal animals were adopted as animals
with cystitis and those whose voiding interval was longer than that were
excluded.

[0897] Collection of Residual Urine

[0898] After the completion of the measurement, the infusion of normal
saline solution was stopped immediately after urination to collect the
residual urine under pentobarbital sodium anesthesia. The collected
residual urine was transferred to the voided urine receiver and recorded
on the chart.

[0899] Analysis Items

[0900] Intravesical pressure one to two hours after the start of the
measurement (pressure during rest and pressure during urination), voiding
interval, voided volume per urination, and residual urine volume

The following value was used as an indicator of the effect on the voiding
interval:

Improvement rate of the urinary function=(Voiding interval of an animal
with cystitis after drug treatment-Voiding interval of an animal with
cystitis before drug treatment)/(Mean voiding interval of normal animals
before drug treatment-Voiding interval of an animal with cystitis before
drug treatment)

The following value was used as an indicator of the effect on the voided
volume per urination:

Improvement rate of the voided volume per urination=(Voided volume per
urination of a rat with cystitis after drug treatment-Voided volume per
urination of an animal with cystitis before drug treatment)/(Mean voided
volume per urination of normal animals before drug treatment-Voided
volume per urination of an animal with cystitis before drug treatment)

[0901] In the above-mentioned test, the compound I-0364 showed
improvements in the urinary function in the voiding interval of 74.8% and
in the voided volume per urination of 88% after oral administration of 30
mg/kg.

Test Example 5

Analgesic Effect in a Seltzer Model

[0902] Preparation of Partial Sciatic Nerve Ligation Model in Rats

[0903] Rats were anaesthetized using isoflurane/O2 inhalation anaesthesia.
After induction of anesthesia, the left thigh was shaved. An incision was
made in the skin just below the hip bone. The muscle was bluntly
dissected to expose the sciatic nerve. One third (1/3) to one half (1/2)
of the sciatic nerve thickness was tightly ligated and the wound was
closed. The right thigh is used as a sham-operated control. The right
thigh undergoes an identical procedure with the left hind limb, however,
the sciatic nerve is not manipulated or ligated.

Evaluation (1)

[0904] Two weeks after nerve ligation, the effect on mechanical allodynia
was assessed using a series of von Frey filaments. For habituation, the
rats were placed into a plastic cage on a wire mesh bottom. The
mechanical sensitivity (mechanical threshold) of the hind paws was
estimated with a series of von Frey filaments (0.4-26 g). The measurement
of mechanical sensitivity of the right and left hind paws was performed
to obtain predose mechanical sensitivity. The rats showing the threshold
change from 0.6 to 2 g (in nerve ligated side) and 8 to 15 g (in sham
operated side) were used in the experiments. On the day before the
experiment, the rats were evaluated with a series of von Frey filaments
to familiarize them with the test procedure. The adopted animal was
administrated with the test compounds. The test compounds were
homogenized with mortar and pestle and suspended or diluted in 0.5%
Methyl Cellulose to prepare 0.1-2.0 mg/mL/kg suspension and orally
administered to rat using a syringe attached with a sonde. Post-dose
mechanical sensitivities of the right and left hind paws were measured at
approximately 1 to 5 hours after drug administration. Percent reversal of
mechanical allodynia for each rat was calculated using the following
formula. The analgesic effects of the compounds were compared.

[0908] Mechanical hyperalgesia was evaluated using an analgesy meter. Two
weeks after nerve ligation, the paw pressure test was performed using an
analgesy meter (stimulus pressure increased 16 g per second) to obtain
paw withdrawal thresholds (PWT). Measurements were made on both sides of
the hind paw and to obtain pre-dose PWT. The rats showing the threshold
change from 60 to 90 g (in nerve ligated side) and 100 to 175 g (in sham
operated side) were used in the experiments. On the day before the
experiment, the rats have their hind paws set on the apparatus to
familiarize them with the test procedure. The adopted animal was
administrated with the test compounds. The test compounds were
homogenized with mortar and pestle and suspended or diluted in 0.5%
Methyl Cellulose to prepare 0.03-100 mg/2 mL/kg suspension and orally
administered to rat using a syringe attached with a sonde. Post-dose PWT
of the right and left hind paws were measured at approximately 1 to 5
hours after drug administration. Percent reversal of mechanical
hyperalgesia for each rat was calculated using the following formula. The
analgesic effects of the compounds were compared.

In the above examination, the analgesic effect of the oral administration
of compound I-0364 at dose of 10 mg/kg was 56.7% reversal at 3 hours.

Test Example 6

CYP3A4 Fluorescent MBI Test

[0909] The CYP3A4 fluorescent MBI test is a test of investigating
enhancement of CYP3A4 inhibition of a compound by a metabolism reaction,
and the test was performed using, as CYP3A4 enzyme expressed in
Escherichia coli and employing, as an index, a reaction in which
7-benzyloxytrifluoromethylchmarin (BFC) is debenzylated by the CYP3A4
enzyme to produce a metabolite, 7-hydroxytrifluoromethylchmarin (HFC)
emitting fluorescent light.

[0911] An enzyme in a K-Pi buffer (pH 7.4) and a test drug solution as a
pre-reaction solution were added to a 96-well plate at the composition of
the pre-reaction, a part of it was transferred to another 96-well plate
so that it was 1/10 diluted by a substrate in a K-Pi buffer, NADPH as a
co-factor was added to initiate a reaction as an index (without
preincubation) and, after a predetermined time of a reaction,
acetonitrile:0.5 mol/L Tris (trishydroxyaminomethane)=4:1 was added to
stop the reaction. In addition, NADPH was added to a remaining
preincubation solution to initiate a preincubation (with preincubation)
and, after a predetermined time of a preincubation, a part was
transferred to another plate so that it was 1/10 diluted with a substrate
and a K-Pi buffer to initiate a reaction as an index. After a
predetermined time of a reaction, acetonitrile:0.5 mol/L Tris
(trishydroxyaminomethane)=4:1 was added to stop the reaction. For the
plate on which each index reaction had been performed, a fluorescent
value of 7-HFC which is a metabolite was measured with a fluorescent
plate reader. (Ex=420 nm, Em=535 nm).

[0912] Addition of only DMSO which is a solvent dissolving a drug to a
reaction system was adopted as a control (100%), remaining activity (%)
was calculated at each concentration of a test drug added as the
solution, and IC50 was calculated by reverse-presumption by a
logistic model using a concentration and an inhibition rate. When a
difference between IC50 values is 5 μM or more, this was defined
as (+) and, when the difference is 3 μM or less, this was defined as
(-).

[0917] Each five kinds of substrates, human hepatic microsome, or a test
drug in 50 mmol/L Hepes buffer as a reaction solution was added to a
96-well plate at the composition as described above, NADPH, as a cofactor
was added to initiate metabolism reactions as markers and, after the
incubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1
(v/v) solution was added to stop the reaction. After the centrifugation
at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the
supernatant was quantified by a fluorescent multilabel counter and
tributamide hydroxide (CYP2CP metabolite), mephenyloin 4' hydroxide
(CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and
terfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.

[0918] Addition of only DMSO being a solvent dissolving a drug to a
reaction system was adopted as a control (100%), remaining activity (%)
was calculated at each concentration of a test drug added as the solution
and IC50 was calculated by reverse presumption by a logistic model
using a concentration and an inhibition rate.

[0919] (Results)

[0920] Compound No. I-0837: five kinds>20 μmol/L

[0921] Compound No. I-2291: five kinds>20 μmol/L

[0922] Compound No. I-1788: five kinds>20 μmol/L

[0923] Compound No. I-1679: five kinds>20 μmol/L

Test Example 8

FAT Test

[0924] 20 μL of freezing-stored rat typhoid bacillus (Salmonella
typhimurium TA98 strain. TA100 strain) is inoculated on 10 mL of a liquid
nutrient medium (2.5% Oxoid nutrient broth No. 2), and this is cultured
before shaking at 37° C. for 10 hours. 9 mL of a bacterial
solution of the TA98 strain is centrifuged (2000×g, 10 minutes) to
remove a culturing solution, the bacteria is suspended in 9 mL of a Micro
F buffer (K2HPO4: 3.5 g/L, KH2PO4: 1 g/L,
(NH4)2SOI: 1 g/L, trisodium citrate dihydrate: 0.25 g/L,
MgSO4.7H2O: 0.1 g/L), the suspension is added to 110 mL of an
Exposure medium (Micro F buffer containing Biotin: 8 μg/mL, histidine:
0.2 μg/mL, glucose: 8 mg/mL), and the TA100 strain is added to 120 mL
of the Exposure medium relative to 3.16 mL of the bacterial solution to
prepare a test bacterial solution. Each 12 μL of a test substance DMSO
solution (8 stage dilution from maximum dose 50 mg/mL at 2-fold ratio),
DMSO as a negative control, 50 μg/mL of 4-nitroquinoline-1-oxide DMSO
solution for the TA98 strain, 0.25 μg/mL of
2-(furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100
strain under the non-metabolism activating condition, 40 μg/mL of
2-aminoanthracene DMSO solution for the TA98 strain, 20 μg/mL of
2-aminoanthracene DMSO solution for the TA100 strain under the metabolism
activating condition as a positive control, and 588 μL of the test
bacterial solution (a mixed solution of 498 μl of the test bacterial
solution and 90 μL of S9 mix under the metabolism activating
condition) are mixed, and this is shaking-cultured at 37° C. for
90 minutes. 460 μL of the bacterial solution exposed to the test
substance is mixed with 2300 μL of an Indicator medium (Micro F buffer
containing biotin: 8 g/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL,
Bromo Cresol Purple: 37.5 μg/mL), each 50 μL is dispensed into
microplate 48 wells/dose, and this is subjected to stationary culturing
at 37° C. for 3 days. Since a well containing a bacterium which
has obtained the proliferation ability by mutation of an amino acid
(histidine) synthesizing enzyme gene turns from purple to yellow due to a
pH change, the bacterium proliferation well which has turned to yellow in
48 wells per dose is counted, and is assessed by comparing with a
negative control group. (-) means that mutagenicity is negative and (+)
is positive.

Test Example 9

Solubility Test

[0925] The solubility of a compound was determined under a condition in
which 1% DMSO was added. 10 mmol/L compound solution was prepared using
DMSO, and then 6 μL of the compound solution was added to 594 μL of
artificial intestinal juice in pH 6.8 (to 250 mL of 0.2 mol/L potassium
dihydrogen phosphate reagent solution was added 118 mL of 0.2 mol/L NaOH
reagent solution and water to provide a final volume of 1000 mL). After
standing at 25 degrees Celsius for 16 hours, the mixed solution was
filtrated with suction. The filtrate was diluted twice with
methanol/water (1/1), and then a concentration in the filtration was
measured with HPLC or LC/MS/MS by the absolute calibration method.

[0926] (Results)

[0927] Compound No. I-0837: >50 μmol/L

[0928] Compound No. I-2291: >50 μmol/L

[0929] Compound No. I-1788: >50 μmol/L

[0930] Compound No. I-1679: >50 μmol/L

Test Example 10

Metabolism Stability Test

[0931] Using commercially available pooled human hepatic microsomes, a
test compound is reacted for a constant time, a remaining rate is
calculated by comparing a reacted sample and an unreacted sample,
thereby, a degree of metabolism in liver is assessed.

[0932] A reaction was performed (oxidative reaction) at 37° C. for
0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a
buffer (50 mmol/L tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10
mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver
microsomes. After the reaction, 50 μL of the reaction solution was
added to 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and
centrifuged at 3000 rpm for 15 minutes. The test compound in the
supernatant was quantified by LC/MS/MS, and a remaining amount of the
test compound after the reaction was calculated, letting a compound
amount at 0 minute reaction time to be 100%.

[0935] For the purpose of assessing risk of an electrocardiogram QT
interval prolongation, effects on delayed rectifier K+ current
(IKr), which plays an important role in the ventricular
repolarization process, is studied using HEK293 cells expressing human
ether-a-go-go related gene (hERG) channel.

[0936] After a cell was retained at a membrane potential of -80 mV by
whole cell patch clamp method using an automated patch clamp system
(PatchXpress 7000A, Axon Instruments Inc.), IKr induced by
depolarization pulse stimulation at +50 mV for 2 seconds and, further,
repolarization pulse stimulation at -50 mV for 2 seconds is recorded.
After the generated current is stabilized, extracellular solution (NaCl:
137 mmol/L, KCl: 4 mmol/L, CaCl2. 2H2O: 1.8 mmol/L,
MgCl2.6H2O: 1 mmol/L, glucose: 10 mmol/L, HEPES
(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4)
in which the test compound had been dissolved at an objective
concentration (1.0 μmol/L) is applied to the cell under the room
temperature condition for 10 minutes. From the recording IKr, an
absolute value of the tail peak current is measured based on the current
value at the resting membrane potential using an analysis software
(DataXpress ver. 1, Molecular Devices Corporation). Further, the %
inhibition relative to the tail peak current before application of the
test substance is calculated, and compared with the vehicle-applied group
(0.1% dimethyl sulfoxide solution) to assess influence of the test
substance on IKr.

Test Example 12

Metabolic Stability Test

[0937] The test compound is reacted for a given period of time using
cryopreserved rat hepatocytes that are prepared and the residual ratio is
calculated based on the comparison between reacted and unreacted samples
to evaluate the degree of hepatic metabolism.

[0938] The compound is reacted in the Williams E medium containing
1.0×106 cells/mL of cryopreserved rat hepatocytes at a
temperature of 37° C. for 0, 1 or 2 hours. After reaction, 50
μL of reaction solution is added to and mixed with 100 μL of a
solution containing methanol and acetonitrile in the proportion of one to
one (v/v) and the mixture is centrifuged at 3000 rpm for 15 minutes. The
test compound contained in the centrifugal supernatant is quantitated
using a LC/MS/MS system and the residual ratio of the test compound after
reaction is calculated regarding the amount of compound after the
reaction for 0 minute as 100%.

Test Example 13

Protein Binding Test

[0939] The unbound fraction of the present compound in serum was measured
using serum of various species.

[0940] The reactive conditions are as follows: Evaluation method,
Equilibrium dialysis; Reaction time, 24 hours; Reaction temperature,
37° C.; Concentration of the present compound, 2 μg/mL The test
solution was added to each serum and the mixture was agitated to prepare
the serum samples at the concentration mentioned above. Each serum sample
was added into one side of the cell and phosphate buffered saline (PBS)
was added into the other side to perform equilibrium dialysis at
37° C. for 24 hours. Then, the concentration of the compounds in
the samples that were obtained from both sides was measured by LC/MS/MS.

[0941] (Result) The ratio of PBS concentration to serum concentration is
expressed as unbound fraction.

[0942] (1) Animals: Mice or SD rats were used (2) Breeding conditions:
Mice or SD rats were allowed to freely take solid food and sterilized tap
water. (3) Dose and grouping: orally or intravenously administered at a
predetermined dose; grouping was as follows (Dose depends on the
compound)

[0943] Oral administration: 0.3 to 30 mg/kg (n=2 to 3)

[0944] Intravenous administration: 0.5 to 10 mg/kg (n=2 to 3)

(4) Preparation of dosing solution: for oral administration, in a
solution or a suspension state; for intravenous administration, in a
solubilized state (5) Administration method: in oral administration,
forcedly administer into ventriculus with oral probe; in intravenous
administration, administer from caudal vein with a needle-equipped
syringe (6) Evaluation items: blood was collected over time, and the
plasma concentration of drug was measured by LC/MS/MS (7) Statistical
analysis: regarding the transition of the plasma concentration of the
present compound, the area under the plasma concentration-time curve
(AUC) was calculated by non-linear least squares program WinNonlin
(Registered trade name), and the bioavailability (BA) was calculated from
the AUCs of the oral administration group and intravenous administration
group

[0951] The compound of the formula (I) and lactose are passed through a 60
mesh sieve. Corn starch is passed through a 120 mesh sieve. These are
mixed with a V-type mixing machine. An aqueous solution of HPC-L (low
viscosity hydroxypropylcellulose) is added to a mixture powder, and this
is kneaded, granulated (extrusion granulation, pore diameter 0.5 to 1
mm), and dried. The resulting dry granule is sieved with a vibration
sieve (12/60 mesh) to obtain a granule.

Preparation Example 2

[0952] A powder for filling into a capsule containing the following
ingredients is prepared.

[0953] The compound of the formula (I), and lactose are passed through a
60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are
mixed, a HPC-L solution is added to the mixed powder, this is kneaded,
granulated, and dried. The resulting dry granule is adjusted in a size,
and 150 mg of it is filled into a No. 4 hard gelatin capsule.

[0955] The compound of the formula (Ia), lactose, microcrystalline
cellulose, CMC-Na (carboxymethylcellulose sodium salt) are passed through
a 60 mesh sieve, and mixed. Magnesium stearate is mixed into a mixture
powder to obtain a mixture powder for tabletting. The present mixed
powder is directly compressed to obtain a 150 mg tablet.

Formulation Example 4

[0956] The following ingredients are warmed, mixed, and sterilized to
obtain an injectable.

[0958] The compound of the formula (I) is added to aqueous-based. The
mixture is irradiated by ultrasonic for 15 minutes and then is
sufficiently stirred to obtain a solution. 5 part of glycerin, 1 part of
kaoline and 5 part of aqueous polyvinyl alcohol are homogeneously mixed
and 1 part of the resulting solution is added to the above solution
including the compound of the formula (I). The obtained solution is mixed
and to give a paste form and the resulting paste is applied to an
non-woven fabric. The resulting composition is covered by polyester film
to give a cataplasm.

[0959] As shown, the compounds described in the present specification
showed inhibiting activity on P2X3 receptor and analgesic activity
and treating effect on overactive bladder. Furthermore, as the compounds
of the invention are effective on P2X3 subtype, the compounds are
also considered to have inhibiting activity on P2X2/3 receptor,
which comprises P2X3 subtype.

INDUSTRIAL APPLICABILITY

[0960] The compounds of the general formula (I), the general formula (II),
the general formula (III), the general formula (IV), the general formula
(VII), the general formula (VIII) and the general formula (IX) have an
antagonistic effect on P2X3 and/or P2X2/3 receptor and are
useful in the treatment of diseases or conditions associated with a
P2X3 and/or P2X2/3 receptor, such as chronic pain, urination
disorder, etc.

TABLE-US-LTS-00001
LENGTHY TABLES
The patent application contains a lengthy table section. A copy of the
table is available in electronic form from the USPTO web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20130172317A1).
An electronic copy of the table will also be available from the USPTO
upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

Patent applications by Tsuyoshi Hasegawa, Toyonaka-Shi JP

Patent applications by Yukio Tada, Toyonaka-Shi JP

Patent applications in class Polycyclo ring system having the additional hetero ring as one of the cyclos

Patent applications in all subclasses Polycyclo ring system having the additional hetero ring as one of the cyclos